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Rare Disease

Rare Disease
Therapies for rare diseases/conditions. Rare Diseases are defined by the Orphan Drug Act of 1983 as those diseases affecting fewer than 200,000 patients in the United States.

Rare Disease Medications

Please select a product from the list to view its approved indications as well as the link to its full prescribing information. The list is not an all-inclusive list of Pfizer medications in a therapeutic area and inclusion of a product within this list should not suggest it is approved for a broad therapeutic area. Please refer to each medication’s individual prescribing information for specific details.

BENEFIX® (nonacog alfa)

These highlights do not include all the information needed to use BENEFIX safety and effectively. See full prescribing information for BENEFIX.

4 CONTRAINDICATIONS

BeneFIX is contraindicated in patients who have manifested life-threatening, immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster protein.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylaxis, have been reported with BeneFIX and have manifested as pruritus, rash, urticaria, hives, facial swelling, dizziness, hypotension, nausea, chest discomfort, cough, dyspnea, wheezing, flushing, discomfort (generalized) and fatigue. Frequently, these events have occurred in close temporal association with the development of factor IX inhibitors.

Closely monitor patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product. Because of the potential for allergic reactions with factor IX concentrates, perform the initial (approximately 10 – 20) administrations of factor IX under medical supervision where proper medical care for allergic reactions could be provided. Advise patients to discontinue use of the product and contact their physician and/or seek immediate emergency care. Immediately discontinue the administration and initiate appropriate treatment if symptoms occur.

BeneFIX contains trace amounts of hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Thromboembolic Complications

There have been post-marketing reports of thrombotic events in patients receiving continuous-infusion BeneFIX through a central venous catheter, including life-threatening superior vena cava (SVC) syndrome in critically ill neonates [see Adverse Reactions (6.2)]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Dosage and Administration (2.1, 2.3)].

5.3 Nephrotic Syndrome

Nephrotic syndrome has been reported following immune tolerance induction with factor IX products in hemophilia B patients with factor IX inhibitors and a history of allergic reactions to factor IX. The safety and efficacy of using BeneFIX for immune tolerance induction have not been established.

5.4 Neutralizing Antibodies (Inhibitors)

Neutralizing antibodies (inhibitors) have been reported following administration of BeneFIX [see Adverse Reactions (6.1)]. Evaluate patients using BeneFIX for the development of factor IX inhibitors by appropriate clinical observations and laboratory tests. If expected plasma factor IX activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor IX inhibitor concentration.

Patients with factor IX inhibitors are at an increased risk of severe hypersensitivity reactions or anaphylaxis upon subsequent challenge with factor IX.2 Evaluate patients experiencing allergic reactions for the presence of an inhibitor and closely monitor patients with inhibitors for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of initial exposure to product [see Warnings and Precautions (5.1)].

5.5 Monitoring Laboratory Tests

  • Monitor patients for factor IX activity levels by the one-stage clotting assay to confirm that adequate factor IX levels have been achieved and maintained, when clinically indicated [see Dosage and Administration (2.1)].
  • Monitor patients for the development of inhibitors if expected factor IX activity plasma levels are not attained, or if bleeding is not controlled with the recommended dose of BeneFIX. Determine factor IX inhibitor levels in Bethesda Units (BUs).

6 ADVERSE REACTIONS

The most serious adverse reactions are systemic hypersensitivity reactions, including bronchospastic reactions and/or hypotension and anaphylaxis and the development of high-titer inhibitors necessitating alternative treatments to factor IX replacement therapy.

The most common adverse reactions observed in clinical trials (frequency > 5% of PTPs or PUPs) were headaches, dizziness, nausea, injections site reaction, injection site pain and skin-related hypersensitivity reactions (e.g., rash, hives).

6.1 Clinical Trials Experience

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

During uncontrolled, open-label clinical studies with BeneFIX conducted in previously treated patients (PTPs), 113 adverse reactions with known or unknown relation to BeneFIX therapy were reported among 38.5% (25 of 65) of subjects (with some subjects reporting more than one event) who received a total of 7,573 infusions. These adverse reactions are summarized in Table 2.

Table 2: Adverse Reactions Reported for PTPs*
Body System Adverse Reaction Number of patients (%)
*
Adverse reactions reported within 72 hours of an infusion of BeneFIX.
Low-titer transient inhibitor formation.
The renal infarct developed in a hepatitis C antibody-positive patient 12 days after a dose of BeneFIX for a bleeding episode. The relationship of the infarct to the prior administration of BeneFIX is uncertain.
Blood and lymphatic system disorders Factor IX inhibition 1 (1.5%)
Eye disorders Blurred vision 1 (1.5%)
Gastrointestinal disorders Nausea 4 (6.2%)
Vomiting 1 (1.5%)
General disorders and administration site conditions Injection site reaction 5 (7.7%)
Injection site pain 4 (6.2%)
Fever 2 (3.1%)
Infections and infestations Cellulitis at IV site 1 (1.5%)
Phlebitis at IV site 1 (1.5%)
Nervous system disorders Headache 7 (10.8%)
Dizziness 5 (7.7%)
Taste perversion (altered taste) 3 (4.6%)
Shaking 1 (1.5%)
Drowsiness 1 (1.5%)
Renal and urinary disorders Renal infarct 1 (1.5%)
Respiratory, thoracic and mediastinal disorders Dry cough 1 (1.5%)
Hypoxia 1 (1.5%)
Chest tightness 1 (1.5%)
Skin and subcutaneous disorders Rash 4 (6.2%)
Hives 2 (3.1%)
Vascular disorders Flushing 2 (3.1%)

In the 63 previously untreated patients (PUPs), who received a total of 5,538 infusions, 10 adverse reactions were reported among 9.5% of the patients (6 out of 63) having known or unknown relationship to BeneFIX. These events are summarized in Table 3.

Table 3: Adverse Reactions Reported for PUPs*
Body System Adverse Reaction Number of Patients (%)
*
Adverse reactions reported within 72 hours of an infusion of BeneFIX.
Two subjects developed high-titer inhibitor formation during treatment with BeneFIX.
Blood and lymphatic system disorders Factor IX inhibition 2 (3.2%)
General disorders and administration site conditions Injection site reaction 1 (1.6%)
Chills 1 (1.6%)
Respiratory, thoracic and mediastinal disorders Dyspnea (respiratory distress) 2 (3.2%)
Skin and subcutaneous disorders Hives 3 (4.8%)
Rash 1 (1.6%)

Immunogenicity

In clinical studies with 65 PTPs (defined as having more than 50 exposure days), a low-titer inhibitor was observed in one patient. The inhibitor was transient, the patient continued on study and had normal factor IX recovery pharmacokinetics at study completion (approximately 15 months after inhibitor detection).

In clinical studies with pediatric PUPs, inhibitor development was observed in 2 out of 63 patients (3.2%), both were high-titer (> 5 BU) inhibitors detected after 7 and 15 exposure days, respectively. Both patients were withdrawn from the study.

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 BeneFIX with the incidence of antibodies to other products may be misleading.

Thromboembolic complications

All subjects participating in the PTP, PUP and surgery studies were monitored for clinical evidence of thrombosis. No thrombotic complications were reported in PUPs or surgery subjects. One PTP subject experienced a renal infarct (see Table 2). Laboratory studies of thrombogenecity (fibrinopeptide A and prothrombin fragment 1 + 2) were obtained in 41 PTPs and 7 surgery subjects prior to infusion and up to 24 hours following infusion. The results of these studies were inconclusive. Out of 29 PTP subjects noted to have elevated fibrinopeptide A levels post-infusion of BeneFIX, 22 also had elevated levels at baseline. Surgery subjects showed no evidence of significant increase in coagulation activation.

6.2 Postmarketing Experience

The following post-marketing adverse reactions have been reported for BeneFIX: inadequate factor IX recovery, inadequate therapeutic response, inhibitor development [see Clinical Pharmacology (12)], anaphylaxis [see Warnings and Precautions (5.1)], angioedema, dyspnea, hypotension, and thrombosis.

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.

There have been post-marketing reports of thrombotic events, including life-threatening SVC syndrome in critically ill neonates, while receiving continuous-infusion BeneFIX through a central venous catheter. Cases of peripheral thrombophlebitis and DVT have also been reported. In some, BeneFIX was administered via continuous infusion, which is not an approved method of administration [see Dosage and Administration (2)]. The safety and efficacy of BeneFIX administration by continuous infusion have not been established [see Warnings and Precautions (5.2)].

1 INDICATIONS AND USAGE

BeneFIX®, Coagulation Factor IX (Recombinant), is a human blood coagulation factor indicated in adult and pediatric patients with hemophilia B (congenital factor IX deficiency or Christmas disease) for:

  • control and prevention of bleeding episodes
  • peri-operative management

Limitations of Use

BeneFIX is NOT indicated for:

  • treatment of other factor deficiencies (e.g., factors II, VII, VIII, and X),
  • treatment of hemophilia A patients with inhibitors to factor VIII,
  • reversal of coumarin-induced anticoagulation,
  • treatment of bleeding due to low levels of liver-dependent coagulation factors.

ELELYSO® (taliglucerase alfa)

These highlights do not include all the information needed to use ELELYSO safety and effectively. See full prescribing information for ELELYSO.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have occurred in some patients treated with ELELYSO. In clinical trials, 2 of 72 (3%) patients treated with ELELYSO experienced signs and symptoms consistent with anaphylaxis. Signs and symptoms of these patients included urticaria, hypotension, flushing, wheezing, chest tightness, nausea, vomiting, and dizziness. These reactions occurred during ELELYSO infusion.

In clinical trials with ELELYSO, 21 of 72 (29%) patients experienced hypersensitivity reactions, including anaphylaxis. Signs and symptoms of hypersensitivity reactions included pruritus, angioedema, flushing, erythema, rash, nausea, vomiting, cough, chest tightness, and throat irritation. These reactions have occurred up to 3 hours after the start of infusion [see Adverse Reactions (6.1)].

Due to the potential for anaphylaxis, appropriate medical support should be readily available when ELELYSO is administered. Observe patients closely for an appropriate period of time after administration of ELELYSO, taking into account the time to onset of anaphylaxis seen in clinical trials. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. If anaphylaxis occurs, ELELYSO should be immediately discontinued, and appropriate medical treatment should be initiated.

Management of hypersensitivity reactions should be based on the severity of the reaction and include slowing or temporary interruption of the infusion and/or administration of antihistamines, antipyretics, and/or corticosteroids for mild reactions. Pretreatment with antihistamines and/or corticosteroids may prevent subsequent hypersensitivity reactions. Patients were not routinely premedicated prior to infusion of ELELYSO during clinical studies. If severe hypersensitivity reactions occur, immediately stop the infusion of ELELYSO and initiate appropriate treatment.

Consider the risks and benefits of re-administering ELELYSO in patients who have experienced a severe reaction associated with ELELYSO. Caution should be exercised upon rechallenge, and appropriate medical support should be readily available [see Adverse Reactions (6.3)].

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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

Clinical Trials of ELELYSO as Initial Therapy

  • Clinical Trial in Patients 19 Years and Older

The safety of ELELYSO at dosages of either 30 units/kg (n=16) or 60 units/kg (n=16) every other week was assessed in 32 adult treatment-naïve patients (aged 19 to 74 years) with Type 1 Gaucher disease in a 9-month double-blind, randomized clinical trial.

Table 1: Adverse Reactions in ≥5% of Treatment-Naïve Adult Patients Treated with ELELYSO
Preferred Term Treatment-Naïve Adults (N=32)
n (%)
Headache 6 (19)
Arthralgia 4 (13)
Fatigue 3 (9)
Nausea 3 (9)
Dizziness 3 (9)
Abdominal pain 2 (6)
Pruritus 2 (6)
Flushing 2 (6)
Vomiting 2 (6)
Urticaria 2 (6)
  • Clinical Trial in Patients 16 Years and Younger

    The safety of ELELYSO at dosages of either 30 units/kg (n=4) or 60 units/kg (n=5) every other week was assessed in 9 pediatric treatment-naïve patients (aged 2 to 13 years) with Type 1 Gaucher disease in a 12-month randomized clinical trial.


    The most common adverse reaction (≥10%) was vomiting, which occurred in 4 of 9 patients. Two patients developed hypersensitivity reactions; one patient experienced severe vomiting and gastrointestinal inflammation, and 1 experienced mild throat irritation and chest discomfort. Both patients responded to treatment with antihistamines and continued ELELYSO treatment.

Clinical Trial in Patients Switching from Imiglucerase Treatment to ELELYSO

The safety of ELELYSO was assessed in 31 patients (26 adult and 5 pediatric patients), ages 6 to 66 years old, with Type 1 Gaucher disease who had previously been receiving treatment with imiglucerase for a minimum of 2 years. ELELYSO was administered for 9 months at the same number of units as each patient's previous imiglucerase dose.

Table 2: Adverse Reactions in ≥10% of Patients Switched from Imiglucerase to ELELYSO (after 9 months on treatment)
Preferred Term Patients Switched from Imiglucerase
(N=31; 26 adults and 5 children)
n (%)
Arthralgia 4 (13)
Headache 4 (13)
Pain in extremity 3 (10)

6.2 Immunogenicity

As with all therapeutic proteins, patients may develop anti-drug antibodies (ADA) to ELELYSO.

In clinical trials of treatment-naïve adults, 17 (53%) of 32 patients developed ADA during treatment with ELELYSO, and 2 (6%) of 32 patients tested positive for ADA at baseline prior to ELELYSO treatment. Of the 17 patients who developed ADA during ELELYSO treatment, 6 patients (35%) developed hypersensitivity reactions, 2 of whom met criteria for anaphylaxis. Two of the 17 patients who developed ADA during ELELYSO treatment discontinued treatment due to hypersensitivity reactions, one of whom had met criteria for anaphylaxis. Of the 2 patients who tested positive for ADA prior to initiation of ELELYSO treatment, one patient developed a hypersensitivity reaction during the first dose of ELELYSO and withdrew from the study. The second patient did not experience a hypersensitivity reaction.

In a clinical trial of treatment-naïve pediatric patients, 2 (22%) of 9 patients developed ADA during treatment with ELELYSO, and one of 9 patients was ADA-positive prior to initiation of ELELYSO. Two of these 3 patients experienced hypersensitivity reactions (1 who developed ADA during treatment and became negative after Week 12 and 1 who was ADA-positive at baseline and became ADA negative after Week 8) and continued treatment with ELELYSO. The third patient who developed ADA during treatment and continued to be ADA-positive until study completion at Week 52 did not experience a hypersensitivity reaction.

In clinical trials of 31 patients (26 adult and 5 pediatric patients) who switched from imiglucerase to ELELYSO treatment, 5 adults (16% of patients) developed ADA during treatment with ELELYSO. Four additional patients (13%, 2 adults and 2 children) tested positive for ADA at baseline but became ADA-negative after the switch to ELELYSO; one of these adult patients subsequently developed ADA to ELELYSO. Two adult patients (1 patient who developed ADA after the switch and 1 who was ADA positive at baseline) experienced hypersensitivity reactions. Both patients continued treatment with ELELYSO.

The relationship between ADA and hypersensitivity reactions is not fully understood. Monitoring for ADA to ELELYSO may be useful in ADA positive patients or in patients who have experienced hypersensitivity reactions to ELELYSO or other enzyme replacement therapies.

Twenty-nine of the 30 adult and pediatric patients who tested positive for ADA were tested for neutralizing antibodies capable of inhibiting the enzymatic activity of ELELYSO. Neutralizing antibodies were detected in 5 (17.2%) of 29 patients, 3 treatment-naïve adult patients, 1 treatment-naïve pediatric patient, and 1 adult patient who switched from imiglucerase. Due to limited available data, it is not possible to determine a relationship between the presence of neutralizing antibodies and therapeutic response with ELELYSO.

Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELELYSO with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ELELYSO in countries where it is marketed. Because these reactions include those reported voluntarily from a population of uncertain size in addition to those from postmarketing studies, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Gastrointestinal disorders: Vomiting, diarrhea

General disorders and administration site conditions: Fatigue

Immune system disorders: Anaphylaxis [see Warning and Precautions (5.1)], Type III immune-mediated fixed drug eruption

Musculoskeletal and connective tissue disorders: Back pain

1 INDICATIONS AND USAGE

ELELYSO is indicated for the treatment of patients with a confirmed diagnosis of Type 1 Gaucher disease.

GENOTROPIN® (somatropin)

These highlights do not include all the information needed to use GENOTROPIN safety and effectively. See full prescribing information for GENOTROPIN.

4 CONTRAINDICATIONS

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 [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 growth hormone 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.

Hypersensitivity

GENOTROPIN is contraindicated in patients with a known hypersensitivity to somatropin or any of its excipients. The 5 mg and 12 mg presentations of GENOTROPIN lyophilized powder contain m-cresol as a preservative. Systemic hypersensitivity reactions have been reported with post-marketing 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.

5 WARNINGS AND PRECAUTIONS

5.1 Acute Critical Illness

Increased mortality 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 has been reported after treatment with pharmacologic amounts of somatropin [see Contraindications (4)]. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. 19%) among somatropin-treated patients (doses 5.3–8 mg/day) compared to those receiving placebo. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients having acute critical illnesses should be weighed against the potential risk.

5.2 Prader-Willi Syndrome in Children

There have been reports of fatalities after initiating therapy with somatropin in pediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnea, or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)].

5.3 Neoplasms

In childhood cancer survivors who were treated with radiation to the brain/head for their first neoplasm and who developed subsequent GHD and were treated with somatropin, an increased risk of a second neoplasm has been reported. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. In adults, it is unknown whether there is any relationship between somatropin replacement therapy and CNS tumor recurrence [see Contraindications (4)]. Monitor all patients with a history of GHD secondary to an intracranial neoplasm routinely while on somatropin therapy for progression or recurrence of the tumor.

Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms.

Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi.

5.4 Impaired Glucose Tolerance and Diabetes Mellitus

Treatment with somatropin may decrease insulin sensitivity, particularly at higher doses in susceptible patients. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment. New-onset Type 2 diabetes mellitus has been reported. Therefore, glucose levels should be monitored periodically in all patients treated with somatropin, especially in those with risk factors for diabetes mellitus, such as obesity, Turner syndrome, or a family history of diabetes mellitus. Patients with preexisting type 1 or type 2 diabetes mellitus or impaired glucose tolerance should be monitored closely during somatropin therapy. The doses of antihyperglycemic drugs (i.e., insulin or oral/injectable agents) may require adjustment when somatropin therapy is instituted in these patients.

5.5 Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin products. Symptoms usually occurred within the first eight (8) weeks after the initiation of somatropin therapy. In all reported cases, IH-associated signs and symptoms rapidly resolved after cessation of therapy or a reduction of the somatropin dose. Funduscopic examination should be performed routinely before initiating treatment with somatropin to exclude preexisting papilledema, and periodically during the course of somatropin therapy. If papilledema is observed by funduscopy during somatropin treatment, treatment should be stopped. If somatropin-induced IH is diagnosed, treatment with somatropin can be restarted at a lower dose after IH-associated signs and symptoms have resolved. Patients with Turner syndrome and Prader-Willi syndrome may be at increased risk for the development of IH.

5.6 Severe Hypersensitivity

Serious systemic hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with post-marketing use of somatropin products. Patients and caregivers should be informed that such reactions are possible and that prompt medical attention should be sought if an allergic reaction occurs [see Contraindications (4)].

5.7 Fluid Retention

Fluid retention during somatropin replacement therapy in adults may occur. Clinical manifestations of fluid retention (e.g., edema, arthralgia, myalgia, nerve compression syndromes including carpal tunnel syndrome/paraesthesias) are usually transient and dose dependent.

5.8 Hypoadrenalism

Patients receiving somatropin therapy who have or are at risk for pituitary hormone deficiency(s) may be at risk for reduced serum cortisol levels and/or unmasking of central (secondary) hypoadrenalism. 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 [see Section 7.1, 11-β Hydroxysteroid Dehydrogenase Type 1].

5.9 Hypothyroidism

Undiagnosed/untreated hypothyroidism may prevent an optimal response to somatropin, in particular, the growth response in children. Patients with Turner syndrome have an inherently increased risk of developing autoimmune thyroid disease and primary hypothyroidism. In patients with growth hormone deficiency, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Therefore, patients treated with somatropin should have periodic thyroid function tests and thyroid hormone replacement therapy should be initiated or appropriately adjusted when indicated.

5.10 Slipped Capital Femoral Epiphyses in Pediatric Patients

Slipped capital femoral epiphyses may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or in patients undergoing rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during somatropin therapy should be carefully evaluated.

5.11 Progression of Preexisting Scoliosis in Pediatric Patients

Progression of scoliosis can occur in patients who experience rapid growth. Because somatropin increases growth rate, patients with a history of scoliosis who are treated with somatropin should be monitored for progression of scoliosis. However, somatropin has not been shown to increase the occurrence of scoliosis. Skeletal abnormalities including scoliosis are commonly seen in untreated Turner syndrome patients. Scoliosis is also commonly seen in untreated patients with Prader-Willi syndrome. Physicians should be alert to these abnormalities, which may manifest during somatropin therapy.

5.12 Otitis Media and Cardiovascular Disorders in Turner Syndrome

Patients with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

5.13 Lipoatrophy

When somatropin is administered subcutaneously at the same site over a long period of time, tissue atrophy may result. This can be avoided by rotating the injection site [see Dosage and Administration. (2.3)].

5.14 Laboratory Tests

Serum levels of inorganic phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and IGF-I may increase during somatropin therapy.

5.15 Pancreatitis

Cases of pancreatitis have been reported rarely in children and adults receiving somatropin treatment, with some evidence supporting a greater risk in children compared with adults. Published literature indicates that girls who have Turner syndrome may be at greater risk than other somatropin-treated children. Pancreatitis should be considered in any somatropin–treated patient, especially a child, who develops persistent severe abdominal pain.

6 ADVERSE REACTIONS

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

6.1 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.

Clinical Trials in children with GHD

In clinical studies with GENOTROPIN in pediatric GHD patients, the following events were reported infrequently: injection site reactions, including pain or burning associated with the injection, fibrosis, nodules, rash, inflammation, pigmentation, or bleeding; lipoatrophy; headache; hematuria; hypothyroidism; and mild hyperglycemia.

Clinical Trials in PWS

In two clinical studies with GENOTROPIN in pediatric patients with Prader-Willi syndrome, the following drug-related events were reported: edema, aggressiveness, arthralgia, benign intracranial hypertension, hair loss, headache, and myalgia.

Clinical Trials in children with SGA

In clinical studies of 273 pediatric patients born small for gestational age treated with GENOTROPIN, the following clinically significant events were reported: mild transient hyperglycemia, one patient with benign intracranial hypertension, two patients with central precocious puberty, two patients with jaw prominence, and several patients with aggravation of preexisting scoliosis, injection site reactions, and self-limited progression of pigmented nevi. Anti-hGH antibodies were not detected in any of the patients treated with GENOTROPIN.

Clinical Trials in children with Turner Syndrome

In two clinical studies with GENOTROPIN in pediatric patients with Turner syndrome, the most frequently reported adverse events were respiratory illnesses (influenza, tonsillitis, otitis, sinusitis), joint pain, and urinary tract infection. The only treatment-related adverse event that occurred in more than 1 patient was joint pain.

Clinical Trials in children with Idiopathic Short Stature

In two open-label clinical studies with GENOTROPIN in pediatric patients with ISS, the most commonly encountered adverse events include upper respiratory tract infections, influenza, tonsillitis, nasopharyngitis, gastroenteritis, headaches, increased appetite, pyrexia, fracture, altered mood, and arthralgia. In one of the two studies, during GENOTROPIN treatment, the mean IGF-1 standard deviation (SD) scores were maintained in the normal range. IGF-1 SD scores above +2 SD were observed as follows: 1 subject (3%), 10 subjects (30%) and 16 subjects (38%) in the untreated control, 0. 23 and the 0.47 mg/kg/week groups, respectively, had at least one measurement; while 0 subjects (0%), 2 subjects (7%) and 6 subjects (14%) had two or more consecutive IGF-1 measurements above +2 SD.

Clinical Trials in adults with GHD

In clinical trials with GENOTROPIN in 1,145 GHD adults, the majority of the adverse events consisted of mild to moderate symptoms of fluid retention, including peripheral swelling, arthralgia, pain and stiffness of the extremities, peripheral edema, myalgia, paresthesia, and hypoesthesia. These events were reported early during therapy, and tended to be transient and/or responsive to dosage reduction.

Table 1 displays the adverse events reported by 5% or more of adult GHD patients in clinical trials after various durations of treatment with GENOTROPIN. Also presented are the corresponding incidence rates of these adverse events in placebo patients during the 6-month double-blind portion of the clinical trials.

Table 1 Adverse Events Reported by ≥ 5% of 1,145 Adult GHD Patients During Clinical Trials of GENOTROPIN and Placebo, Grouped by Duration of Treatment

Double Blind Phase Open Label Phase
GENOTROPIN
Adverse Event Placebo
0–6 mo.
n = 572
% Patients
GENOTROPIN
0–6 mo.
n = 573
% Patients
6–12 mo.
n = 504
% Patients
12–18 mo.
n = 63
% Patients
18–24 mo.
n = 60
% Patients
n = number of patients receiving treatment during the indicated period.
% = percentage of patients who reported the event during the indicated period.
*
Increased significantly when compared to placebo, P≤.025: Fisher´s Exact Test (one-sided)
Swelling, peripheral 5.1 17.5* 5.6 0 1.7
Arthralgia 4.2 17.3* 6.9 6.3 3.3
Upper respiratory infection 14.5 15.5 13.1 15.9 13.3
Pain, extremities 5.9 14.7* 6.7 1.6 3.3
Edema, peripheral 2.6 10.8* 3.0 0 0
Paresthesia 1.9 9.6* 2.2 3.2 0
Headache 7.7 9.9 6.2 0 0
Stiffness of extremities 1.6 7.9* 2.4 1.6 0
Fatigue 3.8 5.8 4.6 6.3 1.7
Myalgia 1.6 4.9* 2.0 4.8 6.7
Back pain 4.4 2.8 3.4 4.8 5.0

Post-Trial Extension Studies in Adults

In expanded post-trial extension studies, diabetes mellitus developed in 12 of 3,031 patients (0.4%) during treatment with GENOTROPIN. All 12 patients had predisposing factors, e.g., elevated glycated hemoglobin levels and/or marked obesity, prior to receiving GENOTROPIN. Of the 3,031 patients receiving GENOTROPIN, 61 (2%) developed symptoms of carpal tunnel syndrome, which lessened after dosage reduction or treatment interruption (52) or surgery (9). Other adverse events that have been reported include generalized edema and hypoesthesia.

Anti-hGH Antibodies

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 GENOTROPIN 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.

In 419 pediatric patients evaluated in clinical studies with GENOTROPIN lyophilized powder, 244 had been treated previously with GENOTROPIN or other growth hormone preparations and 175 had received no previous growth hormone therapy. Antibodies to growth hormone (anti-hGH antibodies) were present in six previously treated patients at baseline. Three of the six became negative for anti-hGH antibodies during 6 to 12 months of treatment with GENOTROPIN. Of the remaining 413 patients, eight (1.9%) developed detectable anti-hGH antibodies during treatment with GENOTROPIN; none had an antibody binding capacity > 2 mg/L. There was no evidence that the growth response to GENOTROPIN was affected in these antibody-positive patients.

Periplasmic Escherichia coli Peptides

Preparations of GENOTROPIN contain a small amount of periplasmic Escherichia coli peptides (PECP). Anti-PECP antibodies are found in a small number of patients treated with GENOTROPIN, but these appear to be of no clinical significance.

6.2 Post-Marketing Experience

Because these adverse events 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 post-marketing use of somatropin products [see Warnings and Precautions (5.6)].

Leukemia has been reported in a small number of GHD children treated with somatropin, somatrem (methionylated rhGH) and GH of pituitary origin. It is uncertain whether these cases of leukemia are related to GH therapy, the pathology of GHD itself, or other associated treatments such as radiation therapy. On the basis of current evidence, experts have not been able to conclude that GH therapy per se was responsible for these cases of leukemia. The risk for children with GHD, if any, remains to be established [see Contraindications (4) and Warnings and Precautions (5.3)].

The following serious adverse reactions have been observed with use of somatropin (including events observed in patients who received brands of somatropin other than GENOTROPIN): acute critical illness [see Warnings and Precautions (5.1)], sudden death [see Warnings and Precautions (5.2)], intracranial tumors [see Warnings and Precautions (5.3)], central hypothyroidism [see Warnings and Precautions (5.9)], cardiovascular disorders, and pancreatitis [see Warnings and Precautions (5.15)].

Slipped capital femoral epiphysis and Legg-Calve-Perthes disease (osteonecrosis/avascular necrosis; occasionally associated with slipped capital femoral epiphysis) have been reported in children treated with growth hormone [see Warnings and Precautions (5.10)]. Cases have been reported with GENOTROPIN.

The following additional adverse reactions have been observed during the appropriate use of somatropin: headaches (children and adults), gynecomastia (children), and significant diabetic retinopathy.

New-onset type 2 diabetes mellitus has been reported.

1 INDICATIONS AND USAGE

1.1 Pediatric Patients

GENOTROPIN is indicated for the treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone.

GENOTROPIN is indicated for the treatment of pediatric patients who have growth failure due to Prader-Willi syndrome (PWS). The diagnosis of PWS should be confirmed by appropriate genetic testing (see CONTRAINDICATIONS).

GENOTROPIN is indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to manifest catch-up growth by age 2 years.

GENOTROPIN is indicated for the treatment of growth failure associated with Turner syndrome.

GENOTROPIN is indicated for the treatment of idiopathic short stature (ISS), also called non-growth hormone-deficient short stature, defined by height standard deviation score (SDS) ≤-2.25, and associated with growth rates unlikely to permit attainment of adult height in the normal range, in pediatric patients whose epiphyses are not closed and for whom diagnostic evaluation excludes other causes associated with short stature that should be observed or treated by other means.

1.2 Adult Patients

GENOTROPIN is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency who meet either of the following two criteria:

Adult Onset (AO): Patients who have growth hormone deficiency, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or

Childhood Onset (CO): Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Patients who were treated with somatropin for growth hormone deficiency in childhood and whose epiphyses are closed should be reevaluated before continuation of somatropin therapy at the reduced dose level recommended for growth hormone deficient adults. According to current standards, confirmation of the diagnosis of adult growth hormone deficiency in both groups involves an appropriate growth hormone provocative test with two exceptions: (1) patients with multiple other pituitary hormone deficiencies due to organic disease; and (2) patients with congenital/genetic growth hormone deficiency.

RAPAMUNE® (sirolimus)

These highlights do not include all the information needed to use RAPAMUNE safety and effectively. See full prescribing information for RAPAMUNE.

WARNING: IMMUNOSUPPRESSION, USE IS NOT RECOMMENDED IN LIVER OR LUNG TRANSPLANT PATIENTS

  • Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use Rapamune® for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient [see Warnings and Precautions (5.1)].

  • The safety and efficacy of Rapamune (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended [see Warnings and Precautions (5.2, 5.3)].
  • Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT)

The use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients. Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant patients, the use of Rapamune in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death [see Warnings and Precautions (5.2)].

  • Lung Transplantation – Bronchial Anastomotic Dehiscence

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen [see Warnings and Precautions (5.3)].

4 CONTRAINDICATIONS

Rapamune is contraindicated in patients with a hypersensitivity to Rapamune [see Warnings and Precautions (5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Increased Susceptibility to Infection and the Possible Development of Lymphoma

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7–3.2% (for Rapamune-treated patients) versus 0.6–0.8% (azathioprine and placebo control) [see Adverse Reactions (6.1) and (6.2)]. Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Rapamune for prophylaxis of organ rejection in patients receiving renal transplants. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

5.2 Liver Transplantation – Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. The use of Rapamune has been associated with adverse outcomes in patients following liver transplantation, including excess mortality, graft loss and hepatic artery thrombosis (HAT).

In a study in de novo liver transplant patients, the use of Rapamune in combination with tacrolimus was associated with excess mortality and graft loss (22% in combination versus 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant patients, the use of Rapamune in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death.

In a clinical study in stable liver transplant patients 6–144 months post-liver transplantation and receiving a CNI-based regimen, an increased number of deaths was observed in the group converted to a Rapamune-based regimen compared to the group who was continued on a CNI-based regimen, although the difference was not statistically significant (3.8% versus 1.4%) [see Clinical Studies (14.5)].

5.3 Lung Transplantation – Bronchial Anastomotic Dehiscence

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when Rapamune has been used as part of an immunosuppressive regimen.

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended.

5.4 Hypersensitivity Reactions

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of Rapamune [see Adverse Reactions (6.7)].

5.5 Angioedema

Rapamune has been associated with the development of angioedema. The concomitant use of Rapamune with other drugs known to cause angioedema, such as angiotensin-converting enzyme (ACE) inhibitors, may increase the risk of developing angioedema. Elevated sirolimus levels (with/without concomitant ACE inhibitors) may also potentiate angioedema [see Drug Interactions (7.2)]. In some cases, the angioedema has resolved upon discontinuation or dose reduction of Rapamune.

5.6 Fluid Accumulation and Impairment of Wound Healing

There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele and wound dehiscence [see Adverse Reactions (6.1)]. mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with Rapamune [see Adverse Reactions (6.1)]. Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion, ascites, and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving Rapamune.

5.7 Hyperlipidemia

Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with Rapamune compared with azathioprine or placebo controls in Studies 1 and 2 [see Adverse Reactions (6.1)]. There were increased incidences of hypercholesterolemia (43–46%) and/or hypertriglyceridemia (45–57%) in patients receiving Rapamune compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune.

Any patient who is administered Rapamune should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines.

In clinical trials of patients receiving Rapamune plus cyclosporine or Rapamune after cyclosporine withdrawal, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels. The concomitant administration of Rapamune and HMG-CoA reductase inhibitors resulted in adverse reactions such as CPK elevations (3%), myalgia (6.7%) and rhabdomyolysis (<1%). In these trials, the number of patients was too small and duration of follow-up too short to evaluate the long-term impact of Rapamune on cardiovascular mortality.

During Rapamune therapy with or without cyclosporine, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents.

5.8 Decline in Renal Function

Renal function should be closely monitored during the co-administration of Rapamune with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and Rapamune were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving Rapamune and cyclosporine compared with control therapies.

Appropriate adjustment of the immunosuppressive regimen, including discontinuation of Rapamune and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function.

In patients with delayed graft function, Rapamune may delay recovery of renal function.

5.9 Proteinuria

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to Rapamune in maintenance renal transplant patients 6–120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to Rapamune compared with CNI continuation [see Clinical Studies (14.4), Adverse Reactions (6.4)]. Patients with the greatest amount of urinary protein excretion prior to Rapamune conversion were those whose protein excretion increased the most after conversion. New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse reaction in 2.2% of the Rapamune conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also reported in 9.2% in the Rapamune conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of Rapamune. The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.

5.10 Latent Viral Infections

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent viral infections. These include BK virus-associated nephropathy, which has been observed in renal transplant patients receiving immunosuppressants, including Rapamune. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss [see Adverse Reactions (6.7)]. Patient monitoring may help detect patients at risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for patients who develop evidence of BK virus-associated nephropathy.

Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal have been reported in patients treated with immunosuppressants, including Rapamune. PML commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated. Consideration should be given to reducing the amount of immunosuppression in patients who develop PML. In transplant patients, physicians should also consider the risk that reduced immunosuppression represents to the graft.

5.11 Interstitial Lung Disease/Non-Infectious Pneumonitis

Cases of interstitial lung disease [ILD] (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the ILD was reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event. In some cases, the ILD has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus concentration increases [see Adverse Reactions (6.7)].

5.12 De Novo Use Without Cyclosporine

The safety and efficacy of de novo use of Rapamune without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with Rapamune, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of Rapamune without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial.

5.13 Increased Risk of Calcineurin Inhibitor-Induced Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura/Thrombotic Microangiopathy

The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) [see Adverse Reactions (6.7)].

5.14 Antimicrobial Prophylaxis

Cases of Pneumocystis carinii pneumonia have been reported in transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease.

5.15 Different Sirolimus Trough Concentration Reported between Chromatographic and Immunoassay Methodologies

Currently in clinical practice, sirolimus whole blood concentrations are being measured by various chromatographic and immunoassay methodologies. Patient sample concentration values from different assays may not be interchangeable [see Dosage and Administration (2.5)].

5.16 Skin Cancer Events

Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor [see Adverse Reactions (6.1, 6.2, 6.7)].

5.17 Interaction with Strong Inhibitors and Inducers of CYP3A4 and/or P-gp

Avoid concomitant use of Rapamune with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) [see Drug Interactions (7.2)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label.

The most common (≥ 30%) adverse reactions observed with Rapamune in clinical studies for organ rejection prophylaxis in recipients of renal transplantation are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia.

The most common (≥ 20%) adverse reactions observed with Rapamune in the clinical study for the treatment of LAM are: stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials for renal transplant rejection prophylaxis: creatinine increased, hypertriglyceridemia, and TTP. In patients with LAM, 11% of subjects discontinued due to adverse reactions, with no single adverse reaction leading to discontinuation in more than one patient being treated with Rapamune.

6.1 Clinical Studies Experience in Prophylaxis of Organ Rejection Following Renal Transplantation

The safety and efficacy of Rapamune Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials [see Clinical Studies (14.1)]. The safety profiles in the two studies were similar.

The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received Rapamune Oral Solution 2 mg/day, 208 received Rapamune Oral Solution 5 mg/day, and 124 received placebo is presented in Table 1 below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following table show the adverse reactions that occurred in at least one of the Rapamune treatment groups with an incidence of ≥ 20%.

The safety profile of the tablet did not differ from that of the oral solution formulation [see Clinical Studies (14.1)].

In general, adverse reactions related to the administration of Rapamune were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. Patients receiving 2 mg of Rapamune Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of Rapamune Oral Solution per day.

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

TABLE 1: ADVERSE REACTIONS OCCURRING AT A FREQUENCY OF ≥ 20% IN AT LEAST ONE OF THE RAPAMUNE TREATMENT GROUPS IN A STUDY OF PROPHYLAXIS OF ORGAN REJECTION FOLLOWING RENAL TRANSPLANTATION (%) AT ≥ 12 MONTHS POST-TRANSPLANTATION (STUDY 2)*
–––Rapamune Oral Solution–––
Adverse Reaction 2 mg/day
(n = 218)
5 mg/day
(n = 208)
Placebo
(n = 124)
*
Patients received cyclosporine and corticosteroids.
Peripheral edema 54 58 48
Hypertriglyceridemia 45 57 23
Hypertension 45 49 48
Hypercholesterolemia 43 46 23
Creatinine increased 39 40 38
Constipation 36 38 31
Abdominal pain 29 36 30
Diarrhea 25 35 27
Headache 34 34 31
Fever 23 34 35
Urinary tract infection 26 33 26
Anemia 23 33 21
Nausea 25 31 29
Arthralgia 25 31 18
Thrombocytopenia 14 30 9
Pain 33 29 25
Acne 22 22 19
Rash 10 20 6
Edema 20 18 15

The following adverse reactions were reported less frequently (≥ 3%, but < 20%)

  • Body as a Whole – Sepsis, lymphocele, herpes zoster, herpes simplex.
  • Cardiovascular – Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia.
  • Digestive System – Stomatitis.
  • Hematologic and Lymphatic System – Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia.
  • Metabolic/Nutritional – Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes mellitus.
  • Musculoskeletal System – Bone necrosis.
  • Respiratory System – Pneumonia, epistaxis.
  • Skin – Melanoma, squamous cell carcinoma, basal cell carcinoma.
  • Urogenital System – Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with Rapamune [see Warnings and Precautions (5.8)], ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia).

Less frequently (< 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus.

Increased Serum Cholesterol and Triglycerides

The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment.

In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol < 200 mg/dL or fasting, total serum triglycerides < 200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol > 240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL), respectively, in patients receiving both Rapamune 2 mg and Rapamune 5 mg compared with azathioprine and placebo controls.

Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42–52% of patients enrolled in the Rapamune arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. In other Rapamune renal transplant studies, up to 90% of patients required treatment for hyperlipidemia and hypercholesterolemia with anti-lipid therapy (e.g., statins, fibrates). Despite anti-lipid management, up to 50% of patients had fasting serum cholesterol levels >240 mg/dL and triglycerides above recommended target levels [see Warnings and Precautions (5.7)].

Abnormal Healing

Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary).

Malignancies

Table 2 below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection [see Clinical Studies (14.1)].

At 24 months (Study 1) and 36 months (Study 2) post-transplant, there were no significant differences among treatment groups.

TABLE 2: INCIDENCE (%) OF MALIGNANCIES IN STUDY 1 (24 MONTHS) AND STUDY 2 (36 MONTHS) POST-TRANSPLANT*,
Rapamune Oral Solution
2 mg/day
Rapamune Oral Solution
5 mg/day
Azathioprine
2–3 mg/kg/day
Placebo
Malignancy Study 1
(n = 284)
Study 2
(n = 227)
Study 1
(n = 274)
Study 2
(n = 219)
Study 1
(n = 161)
Study 2
(n = 130)
*
Patients received cyclosporine and corticosteroids.
Includes patients who prematurely discontinued treatment.
Patients may be counted in more than one category.
Lymphoma/lymphoproliferative disease 0.7 1.8 1.1 3.2 0.6 0.8
Skin Carcinoma
  Any Squamous Cell 0.4 2.7 2.2 0.9 3.8 3.0
  Any Basal Cell 0.7 2.2 1.5 1.8 2.5 5.3
  Melanoma 0.0 0.4 0.0 1.4 0.0 0.0
  Miscellaneous/Not Specified 0.0 0.0 0.0 0.0 0.0 0.8
Total 1.1 4.4 3.3 4.1 4.3 7.7
Other Malignancy 1.1 2.2 1.5 1.4 0.6 2.3

6.2 Rapamune Following Cyclosporine Withdrawal

The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received Rapamune as a maintenance regimen following cyclosporine withdrawal, and 215 patients received Rapamune with cyclosporine therapy [see Clinical Studies (14.2)]. All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg Rapamune groups in Studies 1 and 2.

Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal.

Malignancies

The incidence of malignancies in Study 3 [see Clinical Studies (14.2)] is presented in Table 3.

In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving Rapamune plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the Rapamune with cyclosporine group had a pretransplantation history of skin carcinoma.

TABLE 3: INCIDENCE (%) OF MALIGNANCIES IN STUDY 3 (CYCLOSPORINE WITHDRAWAL STUDY) AT 36 MONTHS POST-TRANSPLANT*,
Malignancy Nonrandomized
(n = 95)
Rapamune with Cyclosporine Therapy
(n = 215)
Rapamune Following Cyclosporine Withdrawal
(n = 215)
*
Patients received cyclosporine and corticosteroids.
Includes patients who prematurely discontinued treatment.
Patients may be counted in more than one category.
Lymphoma/lymphoproliferative disease 1.1 1.4 0.5
Skin Carcinoma
  Any Squamous Cell 3.2 3.3 2.3
  Any Basal Cell 3.2 6.5 2.3
  Melanoma 0.0 0.5 0.0
  Miscellaneous/Not Specified 1.1 0.9 0.0
Total 4.2 7.9 3.7
Other Malignancy 3.2 3.3 1.9

6.3 High-Immunologic Risk Renal Transplant Patients

Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine [see Clinical Studies (14.3)]. Overall, the incidence and nature of adverse reactions was similar to those seen in previous combination studies with Rapamune. The incidence of malignancy was 1.3% at 12 months.

6.4 Conversion from Calcineurin Inhibitors to Rapamune in Maintenance Renal Transplant Population

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant population have not been established [see Clinical Studies (14.4)]. In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to Rapamune (initial target sirolimus concentrations of 12–20 ng/mL, and then 8–20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the Rapamune treatment arm.

The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 25.9% (15/58) versus 13.8% (4/29), graft loss (excluding death with functioning graft loss) was 22.4% (13/58) versus 31.0% (9/29), and death was 15.5% (9/58) versus 3.4% (1/29) in the sirolimus conversion group and CNI continuation group, respectively.

In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the Rapamune conversion arm.

Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus 2.0% (11/551) and comparator 0.4% (1/273) treatment groups was observed with 2:1 randomization scheme.

6.5 Pediatric Renal Transplant Patients

Safety was assessed in a controlled clinical trial in pediatric (< 18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy [see Clinical Studies (14.6)]. The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections.

6.6 Patients with Lymphangioleiomyomatosis

Safety was assessed in a controlled trial involving 89 patients with lymphangioleiomyomatosis, 46 of whom were treated with Rapamune [see Clinical Studies (14.7)]. The adverse drug reactions observed in this trial were consistent with the known safety profile for renal transplant patients receiving Rapamune, with the addition of weight decreased which was reported at a greater incidence with Rapamune when compared to placebo. Adverse reactions occurring at a frequency of ≥ 20% in the Rapamune treatment group and greater than placebo include stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia, and hypercholesterolemia.

6.7 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Rapamune in transplant patients. 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.

  • Body as a Whole – Lymphedema.
  • Cardiovascular – Pericardial effusion (including hemodynamically significant effusions and tamponade requiring intervention in children and adults) and fluid accumulation.
  • Digestive System – Ascites.
  • Hematological/Lymphatic – Pancytopenia, neutropenia.
  • Hepatobiliary Disorders – Hepatotoxicity, including fatal hepatic necrosis, with elevated sirolimus trough concentrations.
  • Immune System – Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis [see Warnings and Precautions (5.4)].
  • Infections – Tuberculosis. BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including Rapamune. This infection may be associated with serious outcomes, including deteriorating renal function and renal graft loss. Cases of progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Rapamune [see Warnings and Precautions (5.10)]. Clostridium difficile enterocolitis.
  • Metabolic/Nutritional – Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia, diabetes mellitus.
  • Nervous system - Posterior reversible encephalopathy syndrome.
  • Respiratory – Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the sirolimus trough concentration increases [see Warnings and Precautions (5.11)]; pulmonary hemorrhage; pleural effusion; alveolar proteinosis.
  • Skin – Neuroendocrine carcinoma of the skin (Merkel cell carcinoma) [see Warnings and Precautions (5.16)], exfoliative dermatitis [see Warnings and Precautions (5.4)].
  • Urogenital – Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis, ovarian cysts, menstrual disorders (including amenorrhea and menorrhagia). Azoospermia has been reported with the use of Rapamune and has been reversible upon discontinuation of Rapamune in most cases.

1 INDICATIONS AND USAGE

1.1 Prophylaxis of Organ Rejection in Renal Transplantation

Rapamune (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

In patients at low-to moderate-immunologic risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation [see Dosage and Administration (2.2)].

In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation [see Dosage and Administration (2.3), Clinical Studies (14.3)].

1.2 Limitations of Use in Renal Transplantation

Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies [see Clinical Studies (14.2)].

In patients at high-immunologic risk, the safety and efficacy of Rapamune used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient [see Clinical Studies (14.3)].

In pediatric patients, the safety and efficacy of Rapamune have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk [see Adverse Reactions (6.5), Clinical Studies (14.6)].

The safety and efficacy of de novo use of Rapamune without cyclosporine have not been established in renal transplant patients [see Warnings and Precautions (5.12)].

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established [see Clinical Studies (14.4)].

1.3 Treatment of Patients with Lymphangioleiomyomatosis

Rapamune (sirolimus) is indicated for the treatment of patients with lymphangioleiomyomatosis (LAM).

SOMAVERT® (pegvisomant)

These highlights do not include all the information needed to use SOMAVERT safety and effectively. See full prescribing information for SOMAVERT.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypoglycemia associated with GH lowering in patients with Diabetes Mellitus

GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may improve in some patients treated with SOMAVERT. Patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary to avoid hypoglycemia in patients with diabetes mellitus.

5.2 Liver Test Elevations

Baseline serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), and alkaline phosphatase (ALP) levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs).

Asymptomatic, transient elevations in transaminases up to 15 times ULN have been observed in < 2% of subjects among two open-label trials (with a total of 147 patients). These reports were not associated with an increase in bilirubin. Transaminase elevations normalized with time, most often after suspending treatment (SOMAVERT should be used in accordance with the information presented in Table 2 with respect to liver test abnormalities while on Somavert treatment).

Table 1. Recommendations of Initiating SOMAVERT Based on Baseline LTs and Periodic Monitoring of LTs During SOMAVERT Treatment
Baseline LT Levels Recommendations
Normal
  • May treat with SOMAVERT.
  • Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months and then bi-annually for the next year.
Elevated, but less than or equal to 3 times ULN May treat with SOMAVERT; however, monitor LTs monthly for at least one year after initiation of therapy and then bi-annually for the next year.
Greater than 3 times ULN
  • Do not treat with SOMAVERT until a comprehensive workup establishes the cause of the patient's liver dysfunction.
  • Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs.
  • Based on the workup, consider initiation of therapy with SOMAVERT.
  • If the decision is to treat, LTs and clinical symptoms should be monitored very closely.

If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT, the following patient management is recommended (Table 2).

Table 2. Clinical Recommendations Based on Liver Test Results While on SOMAVERT
LT Levels and Clinical Signs/Symptoms Recommendations
Greater than or equal to 3 but less than 5 times ULN (without signs/symptoms of hepatitis or other liver injury, or increase in serum TBIL)
  • May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below).
  • Perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.
At least 5 times ULN, or transaminase elevations at least 3 times ULN associated with any increase in serum TBIL (with or without signs/symptoms of hepatitis or other liver injury)
  • Discontinue SOMAVERT immediately.
  • Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal.
  • If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious re-initiation of therapy with SOMAVERT, with frequent LT monitoring.
Signs or symptoms suggestive of hepatitis or other liver injury (e.g., jaundice, bilirubinuria, fatigue, nausea, vomiting, right upper quadrant pain, ascites, unexplained edema, easy bruisability)
  • Immediately perform a comprehensive hepatic workup.
  • If liver injury is confirmed, the drug should be discontinued.

5.3 Cross-Reactivity with GH Assays

SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated.

5.4 Lipohypertrophy

There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection).

5.5 Systemic Hypersensitivity

In subjects with systemic hypersensitivity reactions, caution and close monitoring should be exercised when re-initiating Somavert therapy [see Adverse Reactions (6.3)].

6 ADVERSE REACTIONS

Clinically significant adverse reactions that appear in other section of the labeling include:

Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two patients (0.8%) exposed to SOMAVERT in pre-approval clinical studies. One patient was rechallenged with SOMAVERT, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug.

Elevations in ALT and AST levels were not associated with increased levels of TBIL and ALP, with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of SOMAVERT administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors.

6.1 Clinical Trials Experience

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

In a 12-week randomized, placebo-controlled, double-blind, fixed-dose study of SOMAVERT in subjects with acromegaly, 32 subjects received placebo and 80 subjects received SOMAVERT once daily [see Clinical Studies (14)]. A total of 108 subjects (30 placebo, 78 Somavert) completed 12 weeks of study treatment.

Overall, eight patients with acromegaly (5.3%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations, one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain. Most adverse events did not appear to be dose-dependent. Table 3 shows the incidence of adverse events that were reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study.

Table 3. Adverse Reactions in a 12-week Placebo-Controlled Study in Patients with Acromegaly*
Placebo
n=32
SOMAVERT
10 mg/day
n=26
15 mg/day
n=26
20 mg/day
N=28
*
Table includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo.
The 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1).The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1).
Infection 2 (6%) 6 (23%) 0 0
Pain 2 (6%) 2 (8%) 1 (4%) 4 (14%)
Nausea 1 (3%) 0 2 (8%) 4 (14%)
Diarrhea 1 (3%) 1 (4%) 0 4 (14%)
Abnormal liver function tests 1 (3%) 3 (12%) 1 (4%) 1 (4%)
Flu syndrome 0 1 (4%) 3 (12%) 2 (7%)
Injection site reaction 0 2 (8%) 1 (4%) 3 (11%)
Dizziness 2 (6%) 2 (8%) 1 (4%) 1 (4%)
Accidental injury 1 (3%) 2 (8%) 1 (4%) 0
Back pain 1 (3%) 2 (8%) 0 1 (4%)
Sinusitis 1 (3%) 2 (8%) 0 1 (4%)
Chest pain 0 1 (4%) 2 (8%) 0
Peripheral edema 0 2 (8%) 0 1 (4%)
Hypertension 0 0 2 (8%) 0
Paresthesia 2 (6%) 0 0 2 (7%)

6.2 Immunogenicity

In pre-marketing clinical studies, approximately 17% of the SOMAVERT-treated patients developed low titer, non-neutralizing anti-GH antibodies. Although the presence of these antibodies did not appear to impact the efficacy of SOMAVERT, the long-term clinical significance of these antibodies is not known. No assay for anti-pegvisomant antibodies is commercially available for patients receiving SOMAVERT.

The data above reflect the percentage of patients whose test results were considered positive for antibodies to SOMAVERT. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to SOMAVERT with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

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

Systemic hypersensitivity reactions including anaphylactic reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported in post-marketing use. Some patients required hospitalization. Symptoms did not re-occur in all patients after re-challenge [see Warnings and Precautions (5.5)].

Registry of Patients with Acromegaly Treated with SOMAVERT

ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years).

At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN.

Lipohypertrophy was reported in 6 (0.5%) patients.

MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had "no change"; there was 1 with insufficient data and 16 patients did not have a central MRI reading.

1 INDICATIONS AND USAGE

SOMAVERT is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery or radiation therapy, or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-I (IGF-I) levels.

XYNTHA® Lyophilized Powder (antihemophilic factor (Recombinant))

These highlights do not include all the information needed to use Xyntha Lyophilized Powder safety and effectively. See full prescribing information for Xyntha Lyophilized Powder.

4 CONTRAINDICATIONS

XYNTHA is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Allergic-type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment.

XYNTHA contains trace amounts of hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing Antibodies

Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Warnings and Precautions (5.3)].4,5,6,7,8,9,10,11,12

5.3 Monitoring Laboratory Tests

  • Use individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics to guide dosing and administration.
  • Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [see Dosage and Administration (2)].
  • Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONS

The most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache, arthralgia, pyrexia, and cough.

6.1 Clinical Trials Experience

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

XYNTHA was evaluated in five clinical studies (N=155), four completed studies with adult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age.

The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in previously treated patients (PTPs) with hemophilia A (factor VIII activity in plasma ≤ 2%)who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in previously treated patients with severe or moderately severe hemophilia A (FVIII:C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1161 infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery. [see Clinical Studies (14)]

Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to <16 years of age). A total of 7,150 infusions of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg).

Across all studies, the most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea (8%), vomiting (7%), asthenia (7%), and nausea (6%).

6.2 Immunogenicity

There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).

The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who had previously been treated with factor VIII (PTPs). In the safety and efficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and the experience with predecessor product (with one inhibitor observed in 113 subjects). The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.

None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.

In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.

Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents, 12 to <16 years of age). Of these, one pediatric subject developed an inhibitor.

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, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

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.

The following postmarketing adverse reactions have been reported for XYNTHA:

Anaphylaxis

Inadequate therapeutic response

1 INDICATIONS AND USAGE

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • Control and prevention of bleeding episodes
  • Perioperative management

XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease.

XYNTHA® Solofuse Lyophilized Powder for Solution in Prefilled Dual-chamber Syringe (antihemophilic factor [Recombinant])

These highlights do not include all the information needed to use Xyntha Solofuse Lyophilized Powder for Solution in Prefilled Dual-chamber Syringe safety and effectively. See full prescribing information for Xyntha Solofuse Lyophilized Powder for Solution in Prefilled Dual-chamber Syringe.

4 CONTRAINDICATIONS

XYNTHA is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including hamster proteins.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, are possible with XYNTHA. Inform patients of the early signs or symptoms of hypersensitivity reactions (including hives [rash with itching], generalized urticaria, chest tightness, wheezing, and hypotension) and anaphylaxis. Discontinue XYNTHA if hypersensitivity symptoms occur and administer appropriate emergency treatment.

XYNTHA contains trace amounts of hamster proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.

5.2 Neutralizing Antibodies

Inhibitors have been reported following administration of XYNTHA. Monitor patients for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, perform an assay that measures factor VIII inhibitor concentration to determine if a factor VIII inhibitor is present [see Warnings and Precautions (5.3)].4,5,6,7,8,9,10,11,12

5.3 Monitoring Laboratory Tests

  • Use individual factor VIII values for recovery and, if clinically indicated, other pharmacokinetic characteristics to guide dosing and administration.
  • Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm that adequate factor VIII levels have been achieved and are maintained, when clinically indicated [see Dosage and Administration (2)].
  • Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present when expected factor VIII activity plasma levels are not attained, or when bleeding is not controlled with the expected dose of XYNTHA. Use Bethesda Units (BU) to titer inhibitors.

6 ADVERSE REACTIONS

The most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache, arthralgia, pyrexia, and cough.

6.1 Clinical Trials Experience

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

XYNTHA was evaluated in five clinical studies (N=155), four completed studies with adult and pediatric PTPs and one ongoing study in pediatric PTPs < 6 years of age.

The safety and efficacy of XYNTHA was evaluated in two completed pivotal studies. In the first study (n=94), safety and efficacy were examined in previously treated patients (PTPs) with hemophilia A (factor VIII activity in plasma ≤ 2%) who received XYNTHA for routine prophylaxis and on-demand treatment. Ninety-four subjects received at least one dose of XYNTHA, resulting in a total of 6,775 infusions [see Clinical Studies (14)]. The second study (n=30) examined the use of XYNTHA for surgical prophylaxis in previously treated patients with severe or moderately severe hemophilia A (FVIII: C ≤ 2%) who required elective major surgery and were expected to receive XYNTHA replacement therapy for at least 6 days post-surgery. All subjects received at least one dose of XYNTHA, resulting in 1161 infusions. One subject received XYNTHA for a pre-surgery pharmacokinetic assessment only and did not undergo surgery [see Clinical Studies (14)].

Across all studies, safety was evaluated in 48 previously treated pediatric patients <16 years of age (28 children, < 6 years of age and 20 adolescents, 12 to <16 years of age). A total of 7,150 infusions of XYNTHA were administered with a median dose per infusion of 29 IU/kg (min, max: 9,108 IU/kg).

Across all studies, the most common adverse reactions (≥ 10%) with XYNTHA in adult and pediatric PTPs were headache (26% of subjects), arthralgia (25%), pyrexia (21%), cough (11%). Other adverse reactions reported in ≥ 5% of subjects were: diarrhea (8%), vomiting (7%), asthenia (7%), and nausea (6%).

6.2 Immunogenicity

There is a potential for immunogenicity with therapeutic proteins. The development of factor VIII inhibitors with XYNTHA was evaluated in 144 adult and pediatric PTPs with at least 50 EDs. Laboratory-based assessments for FVIII inhibitor (partial Nijmegen modification of the Bethesda inhibitor assay) were conducted in the clinical studies. The criterion for a positive FVIII result test result was ≥ 0.6 BU/mL. Across all studies, 3 subjects developed factor VIII inhibitors (2.1%).

The clinical studies for XYNTHA examined 124 subjects (94 for bleeding and 30 for surgery) who had previously been treated with factor VIII (PTPs). In the safety and efficacy study, two subjects with inhibitors were observed in 89 subjects (2.2%) who completed ≥ 50 exposure days. In a Bayesian statistical analysis, results from this study were used to update PTP results from a prior supporting study using XYNTHA manufactured at the initial facility (with one de novo and two recurrent inhibitors observed in 110 subjects) and the experience with predecessor product (with one inhibitor observed in 113 subjects). The Bayesian analysis indicated that the population inhibitor rate for XYNTHA, an estimate of the 95% upper limit of the true inhibitor rate, was 4.17%.

None of the PTPs developed anti-CHO (Chinese hamster ovary) or anti-TN8.2 antibodies. One PTP developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.

In the surgery study, one low titer persistent inhibitor and one transient false-positive inhibitor were reported. In this study, one surgical subject developed anti-CHO cell antibodies with no associated allergic reaction. One subject developed anti-FVIII antibodies; but, this subject did not develop an inhibitor.

Across all studies, safety was evaluated in 40 previously treated pediatric patients <16 years of age with at least 50 EDs (25 children, <6 years of age and 15 adolescents, 12 to <16 years of age). Of these, one pediatric subject developed an inhibitor.

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, comparisons of the incidence of antibodies to XYNTHA with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience

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.

The following postmarketing adverse reactions have been reported for XYNTHA:

Anaphylaxis

Inadequate therapeutic response

1 INDICATIONS AND USAGE

XYNTHA, Antihemophilic Factor (Recombinant), is indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:

  • Control and prevention of bleeding episodes
  • Perioperative management

XYNTHA does not contain von Willebrand factor, and therefore is not indicated in patients with von Willebrand's disease.