Humatrope

Humatrope is a prescription medication used in the treatment of growth hormone deficiency in children and adults, short stature associated with Turner syndrome in children, short stature of unknown cause in children, short stature and/or growth failure due to short stature homeobox-containing gene deficiency (SHOX) in children, small for gestational age (SGA) children, and both adult-onset and childhood-onset hypopituitarism.

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

• Lilly, Eli & Company

Humatrope is part of the drug class:

• Somatropin and somatropin agonists

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

• Complications following open heart surgery, abdominal surgery, trauma, and/or acute respiratory failure. Increased mortality has been observed in patients using Humatrope who have acute critical illness including those who have had open heart surgery, abdominal surgery, trauma, and/or acute respiratory failure. The potential benefits of treatment with Humatrope should be weighed against the increased risks in these situations.
• Increased risk of mortality in pediatric patients with Prader-Willi syndrome. There have been reports of fatalities after initiating treatment with Humatrope in pediatric patients with Prader-Willi syndrome. The potential benefits of treatment with Humatrope should be weighed against the increased risks in the setting of pediatric Prader-Willi syndrome. 
• Increased risk of cancer. An increased risk of cancer has been observed in pediatric patients using Humatrope who have previously had cancer and were treated with radiation. If you or your child is a cancer survivor who was treated with radiation, be sure to inform your physician before beginning treatment with Humatrope.
• Reduced insulin sensitivity. Treatment with Humatrope has been associated with reduced insulin sensitivity. Your physician may monitor your blood glucose levels periodically during treatment with Humatrope. Be sure to inform your physician if you have diabetes before beginning therapy with Humatrope. 
• Increased blood pressure inside your head. Increase blood pressure within the skull, also known as intracranial hypertension, has been reported in a small number of patients treated with Humatrope. Patients with Turner syndrome may be at an increased risk for this. Consult with your physician about your risk for developing intracranial hypertension before beginning treatment with Humatrope.
• Reduced effectiveness of Humatrope in the setting of hypothyroidism. If you have hypothyroidism, Humatrope may not be as effective for you. Be sure to inform your physician if you have hypothyroidism before beginning your treatment with Humatrope.
• Leg bone problems in children. Children treated with Humatrope and undergoing rapid growth may experience certain leg bone problems. If you or your child begins to limp or complains of hip and/or knee pain during treatment with Humatrope, inform your physician.
• Progression of pre-existing scoliosis in children. Children with pre-existing scoliosis may experience disease progression during treatment with Humatrope. Pediatric patients with a history of scoliosis should be carefully monitored by a physician during the entire course of treatment with Humatrope.
• Pancreatitis. There is a slightly increased risk of developing pancreatitis during therapy with Humatrope. Females with Turner syndrome maybe at an even greater risk than others treated with Humatrope. Consult with your physician about your level of risk for developing pancreatitis during treatment with Humatrope.

Do not take Humatrope if you:

• are allergic to Humatrope or to any of its ingredients
• have recently had open heart surgery, abdominal surgery, multiple accidental trauma, or acute respiratory failure
• have Prader-Willi syndrome
• have any type of active cancer
• have diabetic eye disease 

Before taking Humatrope, tell your doctor about all of your medical conditions. Especially tell your doctor if you:

• are allergic to Humatrope or to any of its ingredients
• have ever had a stroke
• have diabetes
• have hypothyroidism
• are pregnant or plan to become pregnant
• are breastfeeding or plan to breastfeed
• have any type of active cancer
• have diabetic eye disease
• have pancreatitis
• have scoliosis
• have recently had open heart surgery, abdominal surgery, multiple accidental trauma, and/or acute respiratory failure
• have Prader-Willi syndrome
• have had any bone fractures or other bone problems in your hips and/or legs
• have high blood pressure

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Most Serious And/Or Most Frequently Observed Adverse Reactions

This list presents the most seriousa and/or most frequently observed adverse reactions during treatment with somatropin (including events observed in patients who received brands of somatropin other than Humatrope):

• aSudden death in pediatric patients with Prader-Willi syndrome who had risk factors including severe obesity, history of upper airway obstruction or sleep apnea and unidentified respiratory infection [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
• aIntracranial tumors, in particular meningiomas, in teenagers/young adults treated with radiation to the head for a first neoplasm who subsequently receive somatropin [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS]
• aPancreatitis [see WARNINGS AND PRECAUTIONS]
• a,bGlucose intolerance including impaired glucose tolerance/impaired fasting glucose as well as overt diabetes mellitus [see WARNINGS AND PRECAUTIONS]
• aIntracranial hypertension [see WARNINGS AND PRECAUTIONS]
• aSignificant diabetic retinopathy [see CONTRAINDICATIONS]
• aSlipped capital femoral epiphysis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• aProgression of preexisting scoliosis in pediatric patients [see WARNINGS AND PRECAUTIONS]
• bFluid retention manifested by edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias [see WARNINGS AND PRECAUTIONS]
• aUnmasking of latent central hypothyroidism [see WARNINGS AND PRECAUTIONS]
• aInjection site reactions/rashes and lipoatrophy (as well as rare generalized hypersensitivity reactions) [see WARNINGS AND PRECAUTIONS]

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.

Pediatric Patients

As with all protein pharmaceuticals, a small percentage of patients may develop antibodies to the protein. During the first 6 months of Humatrope therapy in 314 naive patients, only 1.6% developed specific antibodies to Humatrope (binding capacity ≥ 0.02 mg/L). None had antibody concentrations which exceeded 2 mg/L. Throughout 8 years of this same study, two patients (0.6%) had binding capacity > 2 mg/L. Neither patient demonstrated a decrease in growth velocity at or near the time of increased antibody production. It has been reported that growth attenuation from pituitary-derived GH may occur when antibody concentrations are > 1.5 mg/L.

In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy.

In studies with GH deficient pediatric patients, injection site pain was reported infrequently. A mild and transient edema, which appeared in 2.5% of patients, was observed early during the course of treatment.

In a randomized, concurrent-controlled, open-label trial, there was a statistically significant increase in the occurrence of otitis media (43% vs. 26%), ear disorders (18% vs. 5%) and surgical procedures (45% vs. 27%) in patients receiving Humatrope compared with untreated control patients (Table 1). A similar increase in otitis media was observed in an 18-month placebo-controlled trial.

Table 1: Treatment-Emergent Adverse Reactions of Special Interest by Treatment Group in Turner Syndrome

In a randomized, placebo-controlled study of Humatrope treatment (0.22 mg/kg/week) to adult height in patients with idiopathic short stature, the adverse events reported in Humatrope-treated patients (Table 2) were similar to those observed in other pediatric populations treated with Humatrope. Mean serum glucose concentration did not change during Humatrope treatment. Mean fasting serum insulin concentration increased 10% in the Humatrope treatment group at the end of treatment relative to baseline, but remained within the normal reference range. For the same duration of treatment, the mean fasting serum insulin concentration decreased by 2% in the placebo group. The occurrence rates of above-range values for glucose, insulin, and HbA1c were similar in the Humatrope (somatropin)-and placebo-treated groups. No patient developed diabetes mellitus. Consistent with the known mechanism of growth hormone action, Humatrope-treated patients had greater mean increases, relative to baseline, in serum insulin-like growth factor-I (IGF-I) than placebo-treated patients at each study observation. However, there was no significant difference between the Humatrope and placebo treatment groups in the proportion of patients who had at least one serum IGF-I concentration more than 2.0 SD above the age-and gender-appropriate mean (Humatrope: 9 of 35 patients [26%]; placebo: 7 of 28 patients [25%]).

Table 2: Non-serious Clinically Significant Treatment-Emergent Adverse Reactions by Treatment Group in Idiopathic Short Stature

The adverse events observed in the dose-response study (239 patients treated for 2 years) did not indicate a pattern suggestive of a somatropin dose effect. Among Humatrope dose groups, mean fasting blood glucose, mean glycosylated hemoglobin, and the incidence of elevated fasting blood glucose concentrations were similar. One patient developed abnormalities of carbohydrate metabolism (glucose intolerance and high serum HbA1c) on treatment.

Clinically significant adverse events (adverse events previously observed in association with growth hormone treatment in general) were assessed prospectively during the 2-year randomized, open-label study; those observed are presented in Table 3. In both treatment groups, the mean fasting plasma glucose concentration at the end of the first year was similar to the baseline value and remained in the normal range. No patient developed diabetes mellitus or had an above normal value for fasting plasma glucose at the end of one-year of treatment. During the 2 year study period, the proportion of patients who had at least one IGF-I concentration greater than 2.0 SD above the age-and gender-appropriate mean was 10 of 27 [37.0%] for the Humatrope-treated group vs. 0 of 24 patients [0.0%] for the untreated group. The proportion of patients who had at least one IGFBP-3 concentration greater than 2.0 SD above the age and gender appropriate mean was 16 of 27 [59.3%] for the Humatrope treated group vs. 7 of 24 [29.2%] for the untreated group.

Table 3: Clinically Significant Treatment-Emergent Adverse Reactionsa,b by Treatment Group in Patients with SHOX Deficiency

Study 1 - In a 2-year, multicenter, randomized study, 193 non-GH deficient children with short stature born SGA who failed to demonstrate catch-up growth were treated with 2 different Humatrope treatment regimens: a fixed dose of 0.067 mg/kg/day (FHD group) or an individually adjusted dose regimen (IAD group; starting dose 0.035 mg/kg/day which could be increased as early as Month 3 to 0.067 mg/kg/day based on a validated growth prediction model). The most frequently reported adverse events were common childhood infectious diseases. Adverse events possibly/probably related to Humatrope were otitis media and headaches (where there was a suggestion of a modest dose response), and slipped capital femoral epiphysis (1 child) [see WARNINGS AND PRECAUTIONS and section on Most Serious and/or Most Frequently Observed Adverse Reactions]. There were no clear cut cases of new-onset diabetes mellitus, no children treated for hyperglycemia, and no children whose fasting blood glucose exceeded 126 mg/dL at any time during the study. However, 6 children (4 in the FHD group and 2 in the IAD group whose dose was increased from 0.035 mg/kg/day to 0.067 mg/kg/day [one at Month 3 and one at Year 1]) manifested impaired fasting glucose at Year 2. Two of these six children displayed impaired fasting glucose during the study as well, and one of them was required to discontinue Humatrope at Month 15 as a consequence [see WARNINGS AND PRECAUTIONS and section on Most Serious and/or Most Frequently Observed Adverse Reactions]. A modestly dose-dependent increase in mean serum IGF-I SDS concentrations within the reference range was observed; of note, at study completion, 20-25% of these children had serum IGF-I SDS values > +2.

Study 2 - A 2-year, open-label, single-arm study of Humatrope at a dosage of 0.067 mg/kg/day in 35 non-GH deficient children with short stature born SGA who failed to demonstrate catch-up growth did not reveal further safety data of note.

Study 3 - Additional safety information was obtained from 340 short children born SGA followed in an observational study who received an average Humatrope dosage of 0.041 mg/kg/day (maximum dose: 0.084 mg/kg/day) for an average of 3.0 years. Type 2 diabetes mellitus apparently precipitated by Humatrope therapy was reported in a single patient, but appeared to resolve after discontinuation of Humatrope treatment, as the child had a normal oral glucose tolerance test and was receiving no antihyperglycemic medications 9 months after the drug was discontinued. One patient manifested carpal tunnel syndrome [see section on Most Serious and/or Most Frequently Observed Adverse Reactions] and another developed an exacerbation of preexisting scoliosis [see WARNINGS AND PRECAUTIONS and section on Most Serious and/or Most Frequently Observed Adverse Reactions] which may have been related to Humatrope treatment.

In both Study 1 and Study 2, after treatment with Humatrope, bone maturation did not accelerate excessively, and the timing of puberty was age-appropriate in boys and girls.

Therefore, it can be concluded that no novel adverse events potentially related to treatment with Humatrope were reported in either short-term study or were apparent after a review of the post-marketing, observational, safety database.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose can cause tremors or shaking, cold sweats, increased hunger, headache, drowsiness, weakness, dizziness, fast heartbeat, and nausea. Long-term overdose may cause excessive growth.

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 this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of somatropin in children.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of somatropin in the elderly. However, elderly patients are more sensitive to the effects of somatropin and are more likely to have unwanted effects, which may require a dose adjustment in patients receiving somatropin.

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. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

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. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Allergy to benzyl alcohol or
• Allergy to metacresol or
• Brain tumor or
• Cancer, active or
• Closed epiphyses (normal bone growth stopped) in children or
• Diabetic retinopathy (eye condition) or
• Prader-Willi syndrome (a genetic disorder), if severely overweight or have severe breathing problems or
• Severe illness after surgery or major medical emergency (eg, open heart surgery, abdominal surgery, accidental trauma, or respiratory failure)—Should not be used in patients with these conditions.

• Cancer, history of or
• Hypopituitarism (pituitary gland produces low hormone levels) or
• Hypothyroidism (underactive thyroid gland) or
• Otitis media (ear infection) in children, history of or
• Scoliosis (abnormally curved spine)—Use with caution. May make these conditions worse.

• Diabetes, or a family history of—Use with caution. May prevent insulin or other drugs for diabetes from working properly.

• Turner syndrome—Use with caution. May increase risk of having serious problems (eg, pancreas, thyroid, or heart and blood vessel problems, ear or hearing disorders, diabetes, increased pressure in the head, and bone problems such as dislocation in the hip bone or scoliosis).

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:

• Bleeding gums
• bloating or swelling of the face, arms, hands, ankles, lower legs, or feet
• burning, numbness, pain, or tingling in all fingers except smallest finger
• coughing up blood
• difficulty with breathing or swallowing
• difficulty with moving
• dizziness
• increased menstrual flow or vaginal bleeding
• muscle pain or stiffness
• nosebleeds
• not able to move
• pain, swelling, or redness in the joints
• prolonged bleeding from cuts
• rapid weight gain
• red or black, tarry stools
• red or dark brown urine
• tingling of the hands or feet
• unusual weight gain or loss

• 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
• blurred vision
• bone pain
• change in personality
• change in the ability to see colors, especially blue or yellow
• changes in vision
• chills
• confusion
• constipation
• curved spine
• darkened urine
• dry mouth
• fast heartbeat
• fever
• flushed, dry skin
• fracture
• fruit-like breath odor
• headache
• increased hunger
• increased thirst
• increased urination
• indigestion
• limp pain in the hip or knee
• loss of appetite
• loss of consciousness
• nausea
• pains in the stomach, side, or abdomen, possibly radiating to the back
• problems with walking or talking
• seizures
• stomachache
• sweating
• troubled breathing
• tumor
• unusual tiredness or weakness
• vomiting
• weakness
• yellow eyes or skin

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

• Backache
• excessive sweating
• extreme weakness
• increase in hands and feet size
• increased volume of pale, diluted urine
• pain in extremities
• stop in menstruation

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:

• Large, flat, blue, or purplish patches in the skin
• unusually warm skin

• Increased growth of skin lesions
• swelling of the breasts or breast soreness in both females and males

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.

For all patients taking Humatrope (somatropin (rDNA origin)):

• If you have an allergy to human growth hormone or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Brain tumor, cancer, diabetic eye disease, illness shortly after open heart or belly surgery, many injuries from a crash, lung disease, or sleep apnea.

Children:

• If your child has Prader-Willi syndrome and is very overweight, has trouble breathing, or has sleep apnea.
• If your child's bones are no longer growing (closed epiphyses).

This is not a list of all drugs or health problems that interact with Humatrope.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache.
• Feeling tired or weak.
• Muscle or joint pain.
• Muscle stiffness.
• Not able to sleep.
• Upset stomach or throwing up.
• Gas.
• Belly pain.
• Irritation where the shot is given.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Saizen:

• Store at room temperature.
• After mixing, store in a refrigerator. Check with the doctor or pharmacist if you have questions about how long this medicine may be used after mixing.

All other products:

• Store in a refrigerator. Do not freeze.

All products:

• Protect from light.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Humatrope, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Humatrope. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Humatrope.

Review Date: October 4, 2017

Acute Critical Illness Treatment with pharmacologic amounts of somatropin is contraindicated in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure [see Warnings and Precautions (5.1)].

Prader-Willi Syndrome in Children Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Humatrope is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. [See Warnings and Precautions (5.2)].

Active Malignancy In general, somatropin is contraindicated in the presence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Since GH deficiency may be an early sign of the presence of a pituitary tumor (or, rarely, other brain tumors), the presence of such tumors should be ruled out prior to initiation of treatment. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [See Warnings and Precautions (5.3)].

Hypersensitivity Humatrope is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5.6)].

Diabetic Retinopathy Somatropin is contraindicated in patients with active proliferative or severe non-proliferative diabetic retinopathy.

Closed Epiphyses Somatropin should not be used for growth promotion in pediatric patients with closed epiphyses.

NDC 0002-8149-01

MS 8149

24 mg Combination Package

Humatrope®

somatropin (rDNA origin) for injection

24 mg

Cartridge Kit

for use only with the Humatrope® (somatropin [rDNA origin] for injection) pen injection device

Rx only

Refrigerate

Do Not Freeze

Do Not Shake

Kit contains:

One Humatrope Cartridge 24 mg

One Prefilled Diluent Syringe

www.Humatrope.com

Lilly