Pasireotide for Injectable Suspension, for Intramuscular Use

Acromegaly

SIGNIFOR LAR is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

Included as part of the PRECAUTIONS section.

In the event of overdosage, it is recommended that appropriate supportive treatment be initiated, as dictated by the patient's clinical status, until resolution of the symptoms.

Up-to-date information about the treatment of overdose can be obtained from a certified Regional Poison Center. In the event of an overdose, contact the National Capital Poison Center at 1-800-222-1222 or www.poison.org.

Mechanism Of Action

SIGNIFOR LAR is an injectable cyclohexapeptide, somatostatin analog. Pasireotide exerts its pharmacological activity via binding to somatostatin receptors (SSTR). There are five known human somatostatin receptor subtypes: SSTR 1, 2, 3, 4, and 5. These receptor subtypes are expressed in different tissues under normal physiological conditions. Somatostatin analogs bind to SSTRs with different potencies. Pasireotide binds with high affinity to four of the five SSTRs (see Table 3).

Table 3 :  Binding Affinities of Somatostatin (SRIF-14) Pasireotide to the Five Human SSTR Subtypes (SSTR 1-5)

Pharmacodynamics

Somatostatin receptors are expressed in many tissues including neuroendocrine tumors (e.g., growth hormone secreting pituitary adenomas). Pasireotide binds to SSTR2 and SSTR5 subtype receptors which may be relevant for inhibition of GH secretion. In vivo studies show that SIGNIFOR LAR lowers GH and IGF-1 levels in patients with acromegaly.

Individually corrected QT (QTcI) interval was evaluated in a randomized, blinded, crossover study in healthy subjects investigating pasireotide subcutaneous doses of 0.6 mg and 1.95 mg twice daily, respectively. The maximum mean (95% upper confidence bound) placebo-subtracted QTcI change from baseline was 12.7 (14.7) ms and 16.6 (18.6) ms, respectively. Both pasireotide doses decreased heart rate, with a maximum mean (95% lower confidence bound) placebo-subtracted change from baseline of -10.9 (-11.9) beats per minute (bpm) observed at 1.5 hours for pasireotide 0.6 mg twice daily, and -15.2 (-16.5) bpm at 0.5 hours for pasireotide 1.95 mg twice daily.

The predicted peak concentrations for the SIGNIFOR LAR dose of 60 mg in acromegaly patients are similar to the observed peak concentration (24.3 mg/mL) of the subcutaneous Signifor 0.6 mg twice daily dose and below the observed peak concentration (80.6 ng/mL) of the subcutaneous Signifor 1.95 mg twice daily dose.

Pharmacokinetics

No studies have been conducted to evaluate the absolute bioavailability of pasireotide in humans. Food effect is unlikely to occur since SIGNIFOR LAR is administered via a parenteral route.

In healthy volunteers, pasireotide administered as SIGNIFOR LAR is widely distributed with large apparent volume of distribution (Vz/F > 100 L). Distribution between blood and plasma is concentration-independent and shows that pasireotide is primarily located in the plasma (91%). Plasma protein binding is moderate (88%) and independent of concentration.

Pasireotide has low passive permeability and is likely to be a substrate of P-gp (P-glycoprotein), but the impact of P-gp on the ADME (absorption, distribution, metabolism, excretion) of pasireotide is expected to be low. In clinical testing in healthy volunteers, P-gp inhibition did not affect the rate or extent of pasireotide availability [see DRUG INTERACTIONS]. At therapeutic dose levels, pasireotide is not expected to be a substrate of BCRP (breast cancer resistance protein), OCT1 (organic cation transporter 1), or OATP (organic anion-transporting polypeptides) 1B1, 1B3, or 2B1.

Pasireotide was shown to be highly metabolically stable in human liver and kidney microsomes. In healthy volunteers, pasireotide in its unchanged form is the predominant form found in plasma, urine and feces. Somatropin may increase CYP450 enzymes and, therefore, suppression of growth hormone secretion by somatostatin analogs including pasireotide may decrease the metabolic clearance of compounds metabolized by CYP450 enzymes.

Pasireotide is eliminated mainly via hepatic clearance (biliary excretion) with a small contribution of the renal route. In a human ADME study with subcutaneous Signifor with a single dose 0.6 mg, 55.9 ± 6.63% of the radioactivity dose was recovered over the first 10 days post dosing, including 48.3 ± 8.16% of the radioactivity in feces and 7.63 ± 2.03% in urine.

The apparent clearance (CL/F) of SIGNIFOR LAR in healthy volunteers is on average 4.5–8.5 liters/hour.

PK steady state for SIGNIFOR LAR is achieved after three months. Following multiple intramuscular doses every 4 weeks (every 28 days), SIGNIFOR LAR demonstrates approximately dose-proportional PK exposures in the dose range of 20 mg to 60 mg every 4 weeks in patients with acromegaly.

Special Populations

Population PK analyses of SIGNIFOR LAR suggest that race, gender and body weight do not have clinically relevant influence on circulating levels of pasireotide. No dose adjustment is required for demographics.

No studies have been performed in pediatric patients [see Use in Specific Populations].

Age is not a significant covariate in the population PK analysis of patients with acromegaly. Therefore age is not expected to significantly impact circulating levels of pasireotide.

Efficacy and safety data on patients with acromegaly older than 65 years are limited [see Use in Specific Populations].

In a clinical study for a single subcutaneous dose of Signifor in subjects with impaired hepatic function (Child-Pugh A, B and C), subjects with moderate and severe hepatic impairment (Child-Pugh B and C) showed significantly higher exposures than subjects with normal hepatic function. Upon comparing with the control group, AUCinf was increased by 12%, 56%, and 42% and Cmax was increased by 3%, 46%, and 33% respectively, in the mild, moderate, and severe hepatic impairment groups [see Use in Specific Populations and DOSAGE AND ADMINISTRATION].

Clinical studies have not been performed in patients with renal impairment. However, renal clearance has a minor contribution to the elimination of pasireotide in humans. Renal function (creatinine clearance and estimated glomerular filtration rate) is not a covariate in the population PK analysis. Therefore, renal function is not expected to significantly impact the circulating levels of pasireotide [see Use in Specific Populations].

Clinical Studies

Drug-Naïve Patients With Acromegaly

A multicenter, randomized, double-blind study was conducted to assess the safety and efficacy of SIGNIFOR LAR in patients with active acromegaly. A total of 358 patients naïve to drugs used to treat acromegaly were randomized in a 1:1 ratio to SIGNIFOR LAR or another somatostatin analog active comparator.

Randomization was stratified based on previous pituitary surgical status (e.g., at least one prior pituitary surgery versus no prior pituitary surgery).

In the overall study population, 52% were female and the average age of patients was 45 years. Sixty percent of patients were Caucasian, 23% Asian, 12% Other, 3% American Indian and 2% were Black. Forty-two percent of patients had previous pituitary surgery and one patient had a history of pituitary radiation therapy. Median time between diagnosis and trial participation was 6 months. Median GH was 8.8 mcg/L (range: 0.8 – 200 mcg/L) and 10.1 mcg/L (range: 0.6 – 169.6 mcg/L) for SIGNIFOR LAR and active comparator, respectively at baseline. Median standardized IGF-1, defined as IGF-1 value divided by the ULN (i.e., fold above the ULN), was 2.9 (range: 0.9-6.9) and 2.9 (range: 0.8-7.3), for SIGNIFOR LAR and active comparator, respectively, at baseline.

The starting dose of SIGNIFOR LAR was 40 mg. Dose increase was allowed in both arms, at the discretion of investigators, after three and six months of treatment if mean GH was greater than or equal to 2.5 mcg/L and/or IGF-1 was greater than the ULN for age and sex. The maximum allowed dose for SIGNIFOR LAR was 60 mg. The maximum dose of the active comparator was not used in this trial because the trial was multi-national and the maximum dose approved in the US was not approved in all participating countries.

The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5mcg/L and a normal IGF-1 levels at month 12 (age and sex adjusted) (see Table 4, Figure 3 and Figure 4). The proportion of patients achieving this level of control was 31.3% and 19.2% for SIGNIFOR LAR and active comparator, respectively. The changes in mean GH and IGF-1 levels by study visits in subjects with a measurement at these visits (observed cases) are shown in Figures 3 and 4.

Table 4 : Results at Month 12 in Drug-Naïve Patients Study

Figure 3: Mean GH (mcg/L) Levels by Visit in Drug Naïve Patient Study*

* Numbers of patients with a GH value at the given timepoint for Signifor LAR/Active comparator arm are displayed as xxx/xxx on the x axis.

Figure 4: Mean Standardized IGF-1 Levels* By Visit in Drug Naïve Patient Study**

** Numbers of patients with an IGF-1 value at the given timepoint for Signifor LAR/Active comparator arm are displayed as xxx/xxx on the x axis.

Biochemical control was achieved by Month 3 in 30.1% of patients in the SIGNIFOR LAR arm. Ninety-eight percent of patients treated with SIGNIFOR LAR had either a reduction or no change in tumor volume from baseline assessed by MRI at month 12. The median (range) change in tumor volume was a reduction of 39.8% (-97.6% to 16.9%).

Additionally, ring size and acromegaly symptoms score (i.e. headache, fatigue, perspiration, paresthesia, and osteoarthralgia) were followed. At month 12, reductions in ring size and in symptom severity scores in both treatment groups compared to baseline were noted.

Patients With Acromegaly Inadequately Controlled On Other Somatostatin Analogs

A multicenter, randomized, 3-arm trial was conducted in patients with acromegaly inadequately controlled on somatostatin analogs. Patients were randomized to double-blind SIGNIFOR LAR 40 mg (n=65) or SIGNIFOR LAR 60 mg (n=65) or to continued open-label pre-trial somatostatin analog therapies at maximal or near maximal doses (n=68). A total of 181 patients completed the 6 month trial.

Inadequate control was defined as a GH concentration of greater than 2.5 mcg/L (i.e., mean of 5 samples over 2 hours) and a sex-and age-adjusted IGF-1 level greater than 1.3 times the upper limit of normal. Patients were required to have been treated with other somatostatin analogs for at least 6 months prior to randomization. Note that the maximum dose for one of the active comparators approved for use in the United States was not used in this multinational trial; approximately 75% of the population in the comparator group was receiving this active comparator.

In the overall study population, 56% were female and the average age of patients was 45 years. Eighty-one percent of patients were Caucasian, 7% Other, 8% Black, 2% American Indian and 2% Asian. The percentage of patients with previous pituitary surgery in the SIGNIFOR LAR 40 mg and 60 mg arms and in the active control arm was 77%, 63% and 60%, respectively. Three percent (3%) of patients in the SIGNIFOR LAR groups and 7% of patients in the active control arm had prior radiation therapy. Median (range) time from diagnosis to participation in this trial was 50 (10-337) months, 55 (8-357) months, and 54 (8-357) months in the SIGNIFOR LAR 40 mg, 60 mg and the pre-trial therapy arms, respectively. At baseline, median (range) GH was 7.1 (1.0-200) mcg/L, 5.3 (1.4-113.8) mcg/L and 6.1 (1.0-92.4) mcg/L in the SIGNIFOR LAR 40 mg, 60 mg and the pre-trial therapy arms, respectively. Baseline median standardized IGF-1 (defined as IGF-1 value divided by the ULN) values were 2.3, 2.6 and 2.9 in the SIGNIFOR LAR 40 mg, 60 mg and the pre-trial therapy arms, respectively.

The efficacy endpoint was the proportion of patients with a mean GH level less than 2.5 mcg/L and normal IGF-1 levels at week 24. The primary analysis compared SIGNIFOR LAR 60 mg and 40 mg to continued pretrial therapy (i.e., no change in treatment). The proportion of patients achieving biochemical control was 15.4% and 20.0% for SIGNIFOR LAR 40 mg and 60 mg, respectively, at 6 months.

Biochemical control was achieved by Month 3 in 15.4% and 18.5% of patients in the SIGNIFOR LAR 40 mg and 60 mg arms, respectively.

Table 5 : Results at 6 months in Inadequately Controlled Patient Study

Eighty-one percent and 70 percent of patients treated with SIGNIFOR LAR 40 mg and 60 mg, respectively, had either a reduction or no change in tumor volume from baseline assessed by MRI at month 6. The median (range) change in tumor volume was a reduction of -10.4% (-74.5% to 19.4%) and -6.3% (-66.7% to 14.5%) from baseline for SIGNIFOR LAR 40 mg and 60 mg, respectively.

SIGNIFOR® LAR
(sig-na-for L.A.R.)
(pasireotide) for Injectable Suspension, for Intramuscular Use

Read this Patient Information before you start receiving SIGNIFOR LAR, and each time you receive it. There may be new information. This leaflet does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is SIGNIFOR LAR?

SIGNIFOR LAR is a prescription medicine used to treat people with acromegaly for whom surgery has not worked well enough or who cannot have surgery.

It is not known if SIGNIFOR LAR is safe and effective for use in children.

What should I tell my healthcare provider before receiving SIGNIFOR LAR?

Before you receive SIGNIFOR LAR, tell your healthcare provider if you:

• have high blood sugar (hyperglycemia)
• have diabetes
• have or have had heart problems, including an abnormal heart rate or rhythm or problems with the electrical system of your heart (QT prolongation)
• have a low level of potassium or magnesium in your blood
• have liver problems
• have gallstones (cholelithiasis)
• have any other medical conditions
• are pregnant or planning to become pregnant. SIGNIFOR LAR may harm your unborn baby.
• are breastfeeding or planning to breastfeed. It is not known if SIGINFOR LAR passes into your breast milk. You and your healthcare provider should decide if you will receive SIGNIFOR LAR or breastfeed. You should not do both.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

SIGNIFOR LAR and other medicines may affect each other, causing side effects. SIGNIFOR LAR may affect the way other medicines work, and other medicines may affect how SIGNIFOR LAR works. Your healthcare provider may need to change your dose of SIGNIFOR LAR. Especially tell your healthcare provider if you take:

• medicines to control your heart beat (anti-arrhythmics)
• medicines to control your blood pressure (such as beta-blockers or calcium channel blockers)
• medicines to control the potassium and magnesium (electrolytes) levels in your body
• medicines that may affect the way the electrical system of your heart works (QT prolongation)
• cyclosporine
• bromocriptine

Ask your healthcare provider for a list of these medicines if you are not sure.

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine.

How will I receive SIGNIFOR LAR?

• SIGNIFOR LAR must be given by a trained healthcare provider as an injection into the muscle of your buttocks (intramuscularly).
• Your healthcare provider will tell you how much SIGNIFOR LAR you will receive and when you will receive it.
• Your healthcare provider may change your dose of SIGNIFOR LAR or the length of time between your injections. Your healthcare provider will tell you how long you need to receive SIGNIFOR LAR.
• Before you receive SIGNIFOR for the first time, your healthcare provider should do a blood test to check your fasting blood sugar level, electrolyte levels, and your liver function.
• Before you receive SIGNIFOR LAR for the first time and during your treatment, your healthcare provider should do a test to check your heart (electrocardiogram).

What are the possible side effects of SIGNIFOR LAR?

SIGNIFOR LAR may cause serious side effects, including:

• high blood sugar (hyperglycemia) and diabetes. Your healthcare provider should check your blood sugar level before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider if you have any of these symptoms:
  • feel very thirsty
  • urinate more than usual
  • increased appetite with weight loss
  • tiredness

If you get hyperglycemia while receiving SIGNIFOR LAR, your healthcare provider may give you another medicine to lower your blood sugar. Your healthcare provider may also change your dose of SIGNIFOR LAR or advise you to stop receiving it.

• slow heart rate (bradycardia). SIGNIFOR LAR can cause your heart to beat slower. People who have, or have had heart problems, or take certain medicines used to treat slow heart rate or that may cause a slow heart rate, are at higher risk for bradycardia. Tell your healthcare provider if you get any of these symptoms:
  • weakness
  • dizziness
  • fainting or near fainting spells
• changes in the electrical system of your heart (QT interval prolongation). Tell your healthcare provider if you get any of these symptoms:
  • weakness
  • dizziness
  • fainting or near fainting spells
• higher than normal liver function tests. Your healthcare provider should do blood tests to check your liver while you receive SIGNIFOR LAR.
• gallstones (cholelithiasis). Tell your healthcare provider if you get any of these symptoms:
  • sudden pain in your upper right stomach area (abdomen)
  • sudden pain in your right shoulder or between your shoulder blades
  • yellowing of your skin and whites of your eyes
  • fever with chills
  • nausea
• low levels of pituitary hormones (pituitary insufficiency). SIGNIFOR LAR may reduce the pituitary hormones in your body. Your healthcare provider should do a blood test to check your pituitary hormone levels before you start receiving SIGNIFOR LAR and while you receive it. Tell your healthcare provider if you get any of these symptoms:
  • nausea and vomiting
  • tiredness
  • dizziness
  • diarrhea
  • low blood glucose levels
  • loss of appetite
  • weight loss

The most common side effects of SIGNIFOR LAR include:

• diarrhea
• gallstones (cholelithiasis)
• high blood sugar (hyperglycemia)
• diabetes mellitus

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of SIGNIFOR LAR. For more information, ask your healthcare provider or pharmacist.

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

How should I store SIGNIFOR LAR?

• Store SIGNIFOR LAR in the refrigerator between 36°F to 46°F (2°C to 8°C).
• Take SIGNIFOR LAR out of the refrigerator at least 30 minutes before you will receive it to allow it to come to room temperature.
• Do not use SIGNIFOR LAR if it has been out of the refrigerator and at room temperature for more than 24 hours.
• Your healthcare provider should give you SIGNIFOR LAR right away after it is mixed.

Keep SIGNIFOR LAR and all medicines out of the reach of children.

General information about the safe and effective use of SIGNIFOR LAR.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use SIGNIFOR LAR for a condition for which it was not prescribed. Do not give SIGNIFOR LAR to other people, even if they have the same symptoms that you have. It may harm them.

This Patient Information leaflet summarizes the most important information about SIGNIFOR LAR. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about SIGNIFOR LAR that is written for health professionals.

For more information go to www.SIGNIFORLAR.com or call1-888-NOW-NOVA.

What are the ingredients in SIGNIFOR LAR?

Active ingredient: pasireotide

Inactive ingredients:

Vial: Poly(D,L-lactide-co-glycolide)

Prefilled syringe: Mannitol, carboxymethylcellulose sodium, poloxamer 188, water for injections

This Patient Information has been approved by the U.S. Food and Drug Administration.

INSTRUCTIONS FOR PROPER SUSPENSION TECHNIQUE
DEMONSTRATION KIT

ATTENTION

• DO NOT inject/administer the contents of this kit to patients
• This kit is FOR PREPARATION TRAINING ONLY
• Contents NOT SUITABLE FOR HUMAN USE

Read this entire booklet before proceeding. If you have questions about the preparation of SIGNIFOR LAR, please call Novartis Pharmaceuticals Corporation at 1-888-669-6682.

This instruction is being provided as part of a demonstration kit to educate healthcare providers on the proper technique to be employed when reconstituting SIGNIFOR LAR (pasireotide) for injectable suspension with vial adapter. SIGNIFOR LAR should only be administered by a trained healthcare professional.

Important Information for Healthcare Professionals

Successful preparation and administration of SIGNIFOR LAR relies on proper suspension technique.

Follow each of the steps outlined in this instruction to ensure complete saturation of the powder and its uniform suspension.

It is critical that SIGNIFOR LAR and the diluent be allowed to reach room temperature and then be mixed to ensure that the powder is completely suspended.

For more information on SIGNIFOR LAR, see the enclosed full prescribing information or call 1-888-6696682.

Package Contents

• One vial containing Demonstration Placebo
• One prefilled syringe containing diluent solution for reconstitution
• One vial adapter for drug product reconstitution
• One 1.5' x 20 gauge safety injection needle

Step 1

Please note: the demonstration kit does not require refrigerated storage. However, it is essential to remove the SIGNIFOR LAR injection kit from refrigerated storage.

ATTENTION: It is essential to start the reconstitution process only after the SIGNIFOR LAR injection kit reaches room temperature. Let the kit stand at room temperature for a minimum of 30 minutes before reconstitution, but not more than 24 hours.

Note: The SIGNIFOR LAR injection kit can be re-refrigerated if needed.

Step 2

Remove the plastic cap from the vial and clean the rubber stopper of the vial with an alcohol wipe.

Remove the lid film of the vial adapter packaging, but DO NOT remove the vial adapter from its packaging.

Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place. You will hear an audible “click”, when the vial adapter snaps in place.

Lift the packaging off the vial adapter with a vertical movement.

Step 3

Remove the cap from the syringe prefilled with diluent solution and screw the syringe onto the vial adapter.

Slowly push the plunger all the way down to transfer all the diluent solution in the vial.

Step 4

ATTENTION: Keep the plunger pressed and shake the vial moderately in a horizontal direction for a minimumof 30 seconds so that the powder is completely suspended. Repeat moderate shaking for another 30 seconds if the powder is not completely suspended.

Step 5

Turn syringe and vial upside down, slowly pull the plunger back and draw the entire content from the vial into the syringe.

Unscrew the syringe from the vial adapter.

Step 6

Screw the safety injection needle onto the syringe.

Pull the protective cover straight off the needle.

To avoid sedimentation, you may gently shake the syringe to maintain a uniform suspension.

Gently tap the syringe to remove any visible bubbles and expel them from the syringe.

Step 7

DO NOT inject/administer the contents of this kit to patients. This kit is FOR PREPARATION TRAINING ONLY.

Please note SIGNIFOR LAR suspension must only be prepared immediately before administration. Continue to Step 8.

Step 8

Activate the safety guard over the needle, in one of the 2 methods shown:

• either press the hinged section of the safety guard down onto a hard surface (figure A),
• or push the hinge forward with your finger (figure B).

An audible “click” confirms proper activation of safety guard.

Dispose of syringe immediately in a sharps container.

Any unused product or waste material should be disposed of in accordance with local requirements.

Special Precautions for Disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

YOU HAVE NOW COMPLETED THE TRAINING FOR PREPARATION OF SIGNIFOR LAR FOR INJECTABLE SUSPENSION.

WARNING:

THE CONTENTS OF THE DEMONSTRATION KIT ARE NOT SUITABLE FOR HUMAN USE.