Pancreatin

Pronunciation: PAN-kree-a-tin
Generic Name: Pancreatin
Brand Name: Pan-2400

Pancreatin is used for:

Improving digestion of fatty foods.

Pancreatin is a pancreatic enzyme combination. It works by providing extra digestive enzymes, which improves digestion.

Do NOT use Pancreatin if:

• you are allergic to any ingredient in Pancreatin


• you have inflammation of the pancreas

Contact your doctor or health care provider right away if any of these apply to you.

Before using Pancreatin:

Some medical conditions may interact with Pancreatin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances


• if you have Crohn disease, short bowel syndrome, or bowel obstruction (associated with cystic fibrosis)

Some MEDICINES MAY INTERACT with Pancreatin. However, no specific interactions with Pancreatin are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Pancreatin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Pancreatin:

Use Pancreatin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Take Pancreatin with food.


• If you miss a dose of Pancreatin, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Pancreatin.

Important safety information:

• Do not change brands of Pancreatin without checking with your doctor.


• PREGNANCY and BREAST-FEEDING: If you become pregnant while taking Pancreatin, discuss with your doctor the benefits and risks of using Pancreatin during pregnancy. If you are or will be breast-feeding while you are using Pancreatin, check with your doctor or pharmacist to discuss the risks to your baby.

Possible side effects of Pancreatin:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; diarrhea; stomach pain.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Pancreatin side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include diarrhea; intestinal upset.

Proper storage of Pancreatin:

Store Pancreatin at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Pancreatin out of the reach of children and away from pets.

General information:

• If you have any questions about Pancreatin, please talk with your doctor, pharmacist, or other health care provider.


• Pancreatin is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Pancreatin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Pancreatin resources

• Pancreatin Side Effects (in more detail)
• Pancreatin Use in Pregnancy & Breastfeeding
• Pancreatin Drug Interactions
• Pancreatin Support Group
• 0 Reviews for Pancreatin - Add your own review/rating

• Pancreatin Advanced Consumer (Micromedex) - Includes Dosage Information


• Pancreatin Monograph (AHFS DI)


• pancreatin Concise Consumer Information (Cerner Multum)

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Sevikar 20 mg / 5 mg, 40 mg / 5 mg, 40 mg / 10 mg Film-Coated Tablets

1. Name Of The Medicinal Product

Sevikar 20 mg/5 mg film-coated tablets

Sevikar 40 mg/5 mg film-coated tablets

Sevikar 40 mg/10 mg film-coated tablets

2. Qualitative And Quantitative Composition

Sevikar 20 mg/5 mg film-coated tablets:

Each film-coated tablet of Sevikar contains 20 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).

Sevikar 40 mg/5 mg film-coated tablets:

Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 5 mg of amlodipine (as amlodipine besilate).

Sevikar 40 mg/10 mg film-coated tablets:

Each film-coated tablet of Sevikar contains 40 mg of olmesartan medoxomil and 10 mg of amlodipine (as amlodipine besilate).

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Sevikar 20 mg/5 mg film-coated tablets:

White, round, film-coated tablet with C73 debossed on one side.

Sevikar 40 mg/5 mg film-coated tablets:

Cream, round, film-coated tablet with C75 debossed on one side.

Sevikar 40 mg/10 mg film-coated tablets:

Brownish-red, round, film-coated tablet with C77 debossed on one side.

4. Clinical Particulars

4.1 Therapeutic Indications

Treatment of essential hypertension.

Sevikar is indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil or amlodipine monotherapy (see section 4.2 and section 5.1).

4.2 Posology And Method Of Administration

Adults

The recommended dosage of Sevikar is 1 tablet per day.

Sevikar 20 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil or 5 mg amlodipine alone.

Sevikar 40 mg/5 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 20 mg/5 mg.

Sevikar 40 mg/10 mg may be administered in patients whose blood pressure is not adequately controlled by Sevikar 40 mg/5 mg.

A step-wise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.

For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Sevikar tablets containing the same component doses.

Sevikar can be taken with or without food.

Elderly (age 65 years or over)

No adjustment of the recommended dose is generally required for elderly patients (see section 5.2).

If up-titration to the maximum dose of 40 mg olmesartan medoxomil daily is required, blood pressure should be closely monitored.

Renal impairment

The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 20 – 60 mL/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of Sevikar in patients with severe renal impairment (creatinine clearance < 20 mL/min) is not recommended (see 4.4, 5.2).

Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.

Hepatic impairment

Sevikar should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.4, 5.2).

In patients with moderate hepatic impairment, an initial dose of 10 mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment.

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Sevikar should therefore be administered with caution in these patients.

Paediatric population

The safety and efficacy of Sevikar in children and adolescents below 18 years has not been established. No data are available.

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

4.3 Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivatives or to any of the excipients (see section 6.1).

Second and third trimesters of pregnancy (see sections 4.4 and 4.6).

Severe hepatic insufficiency and biliary obstruction (see section 5.2).

Due to the component amlodipine Sevikar is also contraindicated in patients with:

- severe hypotension.

- shock (including cardiogenic shock).

- obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).

- haemodynamically unstable heart failure after acute myocardial infarction

4.4 Special Warnings And Precautions For Use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sevikar or close medical supervision at the start of the treatment is recommended.

Other conditions with stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system, such as angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

When Sevikar is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Sevikar is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections 4.2, 5.2). There is no experience of the administration of Sevikar in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance < 12 mL/min).

Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2). Care should be taken when Sevikar is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2). Use of Sevikar in patients with severe hepatic impairment is contraindicated (see section 4.3).

Hyperkalaemia:

As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure (see section 4.5). Close monitoring of serum potassium levels in at-risk patients is recommended.

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (heparin, etc.) should be undertaken with caution and with frequent monitoring of potassium levels.

Lithium:

As with other angiotensin II receptor antagonists, the concomitant use of Sevikar and lithium is not recommended (see section 4.5).

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Sevikar as with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sevikar is not recommended in such patients.

Heart failure:

As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see section 5.1).

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of Sevikar can be somewhat less in black patients than in non-black patients, possibly because of a higher prevalence of low-renin status in the black hypertensive population.

Elderly patients

In the elderly, increase of the dosage should take place with care (see section 5.2).

Pregnancy:

Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other:

As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Potential interactions related to the Sevikar combination:

To be taken into account with concomitant use

Other antihypertensive agents:

The blood pressure lowering effect of Sevikar can be increased by concomitant use of other antihypertensive medicinal products (e.g. alpha blockers, diuretics).

Potential interactions related to the olmesartan medoxomil component of Sevikar

Concomitant use not recommended

Medicinal products affecting potassium levels:

Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Sevikar, monitoring of serum potassium levels is recommended.

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II antagonists. Therefore concomitant use of Sevikar and lithium is not recommended (see section 4.4). If concomitant use of Sevikar and lithium proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Non-steroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs:

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.

Additional information

After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.

Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.

Potential interactions related to the amlodipine component of Sevikar:

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors:

With concomitant use of CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased by 22% and 50 % respectively. However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i.e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such interaction have been reported.

CYP3A4 inducers:

There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (i.e. rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

In clinical interaction studies, grapefruit juice, cimetidine, aluminium/ magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or cyclosporin.

There is no effect of amlodipine on laboratory parameters.

4.6 Pregnancy And Lactation

Pregnancy (see section 4.3)

There are no data about the use of Sevikar in pregnant patients. Animal reproductive toxicity studies with Sevikar have not been performed.

Olmesartan medoxomil (active ingredient of Sevikar)

The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II antagonists therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See section 5.3).

Should exposure to angiotensin II antagonists have occurred from the second trimester on, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension (see sections 4.3 and 4.4).

Amlodipine (active ingredient of Sevikar)

Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery.

As a consequence, Sevikar is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Lactation

Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk.

Because no information is available regarding the use of olmesartan and amlodipine during breast-feeding, Sevikar is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7 Effects On Ability To Drive And Use Machines

Sevikar can have minor or moderate influence on the ability to drive and use machines.

Dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.

4.8 Undesirable Effects

Sevikar:

The most commonly reported adverse reactions during treatment with Sevikar are peripheral oedema (11.3%), headache (5.3%) and dizziness (4.5%).

Adverse reactions from Sevikar in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and amlodipine based on the known safety profile of these substances.

The following terminologies have been used in order to classify the occurrence of adverse reactions:

Very common (

Common (

Uncommon (

Rare (

Very rare (<1/10,000), not known (cannot be estimated from the available data)

MedDRA System Organ Class	Adverse reactions	Frequency
Olmesartan/Amlodipine combination	Olmesartan	Amlodipine
Blood and lymphatic system disorders	Leukocytopenia			Very rare
Thrombocytopenia		Uncommon	Very rare
Immune system disorders	Allergic reaction /Drug hypersensitivity	Rare		Very rare
Anaphylactic reaction		Uncommon
Metabolism and nutrition disorders	Hyperglycaemia			Very rare
Hyperkalaemia	Uncommon	Rare
Hypertriglyceridaemia		Common
Hyperuricaemia		Common
Psychiatric disorders	Confusion			Rare
Depression			Uncommon
Insomnia			Uncommon
Irritability			Uncommon
Libido decreased	Uncommon
Mood changes (including anxiety)			Uncommon
Nervous system disorders	Dizziness	Common	Common	Common
Dysgeusia			Uncommon
Headache	Common	Common	Common (especially at the beginning of treatment)
Hypertonia			Very rare
Hypoaesthesia	Uncommon		Uncommon
Lethargy	Uncommon
Paraesthesia	Uncommon		Uncommon
Peripheral neuropathy			Very rare
Postural dizziness	Uncommon
Sleep disorder			Uncommon
Somnolence			Common
Syncope	Rare		Uncommon
Tremor			Uncommon
Eye disorders	Visual disturbance (including diplopia)			Uncommon
Ear and labyrinth disorders	Tinnitus			Uncommon
Vertigo	Uncommon	Uncommon
Cardiac disorders	Angina pectoris		Uncommon	Uncommon (incl. aggravation of angina pectoris)
Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)			Very rare
Myocardial infarction			Very rare
Palpitations	Uncommon		Uncommon
Tachycardia	Uncommon
Vascular disorders	Hypotension	Uncommon	Rare	Uncommon
Orthostatic hypotension	Uncommon
Flushing	Rare		Common
Vasculitis			Very rare
Respiratory, thoracic and mediastinal disorders	Bronchitis		Common
Cough	Uncommon	Common	Very rare
Dyspnoea	Uncommon		Uncommon
Pharyngitis		Common
Rhinitis		Common	Uncommon
Gastrointestinal disorders	Abdominal pain		Common	Common
Altered bowel habits (including diarrhoea and constipation)			Uncommon
Constipation	Uncommon
Diarrhoea	Uncommon	Common
Dry mouth	Uncommon		Uncommon
Dyspepsia	Uncommon	Common	Uncommon
Gastritis			Very rare
Gastroenteritis		Common
Gingival hyperplasia			Very rare
Nausea	Uncommon	Common	Common
Pancreatitis			Very rare
Upper abdominal pain	Uncommon
Vomiting	Uncommon	Uncommon	Uncommon
Hepato-biliary disorders	Hepatic enzymes increased		Common	Very rare (mostly consistent with cholestasis)
Hepatitis			Very rare
Jaundice			Very rare
Skin and subcutaneous tissue disorders	Alopecia			Uncommon
Angioneurotic oedema		Rare	Very rare
Allergic dermatitis		Uncommon
Erythema multiforme			Very rare
Exanthema		Uncommon	Uncommon
Exfoliative dermatitis			Very rare
Hyperhydrosis			Uncommon
Photosensitivity			Very rare
Pruritus		Uncommon	Uncommon
Purpura			Uncommon
Quincke oedema			Very rare
Rash	Uncommon	Uncommon	Uncommon
Skin discoloration			Uncommon
Stevens-Johnson syndrome			Very rare
Urticaria	Rare	Uncommon

Increlex

mecasermin

Dosage Form: injection, solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Increlex

Severe Primary IGF-1 Deficiency (Primary IGFD)

Increlex® (mecasermin [rDNA origin] injection) is indicated for the treatment of:

• growth failure in children with severe primary IGF-1 deficiency.


• growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH.

Severe Primary IGF-1 deficiency (IGFD) is defined by:

• height standard deviation score ≤ –3.0 and


• basal IGF-1 standard deviation score ≤ –3.0 and


• normal or elevated growth hormone (GH).

Severe Primary IGFD includes classical and other forms of growth hormone insensitivity. Patients with Primary IGFD may have mutations in the GH receptor (GHR), post-GHR signaling pathway including the IGF-1 gene. They are not GH deficient, and therefore, they cannot be expected to respond adequately to exogenous GH treatment.

Increlex® is not intended for use in subjects with secondary forms of IGF-1 deficiency, such as GH deficiency, malnutrition, hypothyroidism, or chronic treatment with pharmacologic doses of anti-inflammatory steroids. Thyroid and nutritional deficiencies should be corrected before initiating Increlex® treatment.

Limitations of use: Increlex® is not a substitute to GH for approved GH indications.

Increlex Dosage and Administration

Dosage

Preprandial glucose monitoring is recommended at treatment initiation and until a well tolerated dose is established. If frequent symptoms of hypoglycemia or severe hypoglycemia occur, preprandial glucose monitoring should continue. The dosage of Increlex® should be individualized for each patient. The recommended starting dose of Increlex® is 0.04 to 0.08 mg/kg (40 to 80 micrograms/kg) twice daily by subcutaneous injection. If well-tolerated for at least one week, the dose may be increased by 0.04 mg/kg per dose, to the maximum dose of 0.12 mg/kg given twice daily. Doses greater than 0.12 mg/kg given twice daily have not been evaluated in children with Primary IGFD and, due to potential hypoglycemic effects, should not be used. If hypoglycemia occurs with recommended doses despite adequate food intake, the dose should be reduced. Increlex® should be administered shortly before or after (± 20 minutes) a meal or snack. If the patient is unable to eat shortly before or after a dose for any reason, that dose of Increlex® should be withheld. Subsequent doses of Increlex® should never be increased to make up for one or more omitted dose.

Administration

Increlex® is administered by subcutaneous injection.

Increlex® injection sites should be rotated to a different site (upper arm, thigh, buttock or abdomen) with each injection to avoid lipohypertrophy.

Increlex® should be administered using sterile disposable syringes and needles. The syringes should be of small enough volume so that the prescribed dose can be withdrawn from the vial with accuracy.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Dosage Forms and Strengths

Increlex® is a sterile solution available at a concentration of 10 mg per mL (40 mg per vial).

Contraindications

Active or Suspected Neoplasia

Increlex® is contraindicated in the presence of active or suspected malignancy, and therapy should be discontinued if evidence of malignancy develops.

Known Hypersensitivity

 Increlex® should not be used by patients who are allergic to mecasermin (rhIGF-1) or any of the inactive ingredients in Increlex®, or who have experienced a severe hypersensitivity to Increlex® [see Warnings and Precautions (5.2) and Adverse Reactions (6.2)]

Intravenous Administration

Intravenous administration of Increlex® is contraindicated.

Closed Epiphyses

Increlex® should not be used for growth promotion in patients with closed epiphyses.

Warnings and Precautions

Hypoglycemia

Because Increlex® has insulin-like hypoglycemic effects it should be administered shortly before or after (± 20 minutes) a meal or snack. Glucose monitoring and Increlex® dose titration are recommended until a well tolerated dose is established (see Dosage 2.1) and subsequently as medically indicated. Special attention should be paid to small children because their oral intake may not be consistent. Patients should avoid engaging in any high-risk activities (e.g., driving, etc.) within 2 to 3 hours after dosing, particularly during the initiation of Increlex® treatment until tolerability and a stable dose have been established [see Adverse Reactions (6.1)]. Increlex® should not be administered when the meal or snack is omitted. The dose of Increlex® should never be increased to make up for one or more omitted doses.

Hypersensitivity and Allergic Reactions, including Anaphylaxis

 Allergic reactions to Increlex® have been reported post-marketing. They range from localized (injection site) reactions to systemic reactions, including anaphylaxis requiring hospitalization. Parents and patients should be informed that such reactions are possible and that if a systemic allergic reaction occurs treatment should be interrupted and prompt medical attention should be sought. [see Contraindications (4.2) and Adverse Reactions (6.2, 6.3)]

Intracranial Hypertension

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting have occurred in patients treated with Increlex®, similar to patients treated with therapeutic doses of growth hormone. IH-associated signs and symptoms resolved after interruption of dosing. Funduscopic examination is recommended at the initiation and periodically during the course of Increlex® therapy. [see Adverse Reactions (6.2)]

Lymphoid Tissue Hypertrophy

Lymphoid tissue (e.g., tonsillar and adenoidal) hypertrophy associated with complications, such as snoring, sleep apnea, and chronic middle-ear effusions have been reported with the use of Increlex®. Patients should have periodic examinations to rule out such potential complications and receive appropriate treatment if necessary. [see Adverse Reactions (6.2)]

Slipped Capital Femoral Epiphysis

Slipped capital femoral epiphysis may occur in patients who experience rapid growth. Any pediatric patient with the onset of a limp or complaints of hip or knee pain during Increlex® therapy should be carefully evaluated.

Progression of Preexisting Scoliosis

Progression of scoliosis may occur in patients who experience rapid growth. Because Increlex® increases growth rate, patients with a history of scoliosis who are treated with Increlex® should be monitored for progression of scoliosis.

Benzyl Alcohol

Benzyl alcohol, a component of this product, has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.

Adverse Reactions

Most Serious and/or Most Frequently Observed Adverse Reactions:

• Hypoglycemia [see Warnings and Precautions (5.1), Adverse Reaction (6.2)]


• Hypersensitivity and Allergic Reactions, including Anaphylaxis [see Contraindications (4.2), Warnings and Precautions (5.2), Adverse Reaction (6.2)]


• Intracranial hypertension (IH) [see Warnings and Precautions (5.3), Adverse Reaction (6.2]


• Tonsillar and Adenoidal Hypertrophy and related complications [see Warnings and Precautions (5.4) , Adverse Reactions (6.2)]

Clinical Trial 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.

In clinical studies of 71 subjects with Primary IGFD treated for a mean duration of 3.9 years and representing 274 subject-years, no subjects withdrew from any clinical study because of adverse reactions. Adverse reactions to Increlex® treatment that occurred in 5% or more of these study participants are listed below by organ class.

 

Metabolism and Nutrition Disorders: hypoglycemia

 

General Disorders and Administrative Site Conditions: lipohypertrophy, bruising

 

Infections and Infestations: otitis media, serous otitis media

 

Respiratory, Thoracic and Mediastinal Disorders: snoring, tonsillar hypertrophy

 

Nervous System Disorders: headache, dizziness, convulsions

 

Gastrointestinal Disorders: vomiting

 

Ear and Labyrinth Disorders: hypoacusis, fluid in middle ear, ear pain, abnormal tympanometry

 

Cardiac Disorders: cardiac murmur

 

Musculoskeletal and Connective Tissue Disorders: arthralgia, pain in extremity

 

Blood and Lymphatic System Disorders: thymus hypertrophy

 

Surgical and Medical Procedures: ear tube insertion

Hypoglycemia was reported by 30 subjects (42%) at least once during their course of therapy. Most cases of hypoglycemia were mild or moderate in severity. Five subjects had severe hypoglycemia (requiring assistance and treatment) on one or more occasion and 4 subjects experienced hypoglycemic seizures/loss of consciousness on one or more occasion. Of the 30 subjects reporting hypoglycemia, 14 (47%) had a history of hypoglycemia prior to treatment. The frequency of hypoglycemia was highest in the first month of treatment, and episodes were more frequent in younger children. Symptomatic hypoglycemia was generally avoided when a meal or snack was consumed either shortly (i.e., 20 minutes) before or after the administration of Increlex®.

Tonsillar hypertrophy was noted in 11 (15%) subjects in the first 1 to 2 years of therapy with lesser tonsillar growth in subsequent years. Tonsillectomy or tonsillectomy/adenoidectomy was performed in 7 subjects; 3 of these had obstructive sleep apnea, which resolved after the procedure in all three cases.

Intracranial hypertension occurred in three subjects. In two subjects the events resolved without interruption of Increlex® treatment. Increlex® treatment was discontinued in the third subject and resumed later at a lower dose without recurrence.

Mild elevations in the serum AST and LDH were found in a significant proportion of patients before and during treatment. Rise in levels of these serum enzymes did not lead to treatment discontinuation. ALT elevations were occasionally noted during treatment.

Renal and splenic lengths (measured by ultrasound) increased rapidly on Increlex® treatment during the first years of therapy. This lengthening slowed down subsequently; though in some patients, renal and/or splenic length reached or surpassed the 95th percentile. Renal function (as defined by serum creatinine and calculated creatinine clearance) was normal in all patients, irrespective of renal growth.

Elevations in cholesterol and triglycerides to above the upper limit of normal were observed before and during treatment.

Echocardiographic evidence of cardiomegaly/valvulopathy was observed in a few individuals without associated clinical symptoms. The relation of these cardiac changes to drug treatment cannot be assessed due to underlying disease and the lack of a control group.

Thickening of the soft tissues of the face was observed in several patients and should be monitored during Increlex® treatment.

As with all therapeutic proteins, there is potential for immunogenicity. Anti-IGF-1 antibodies were present at one or more of the periodic assessments in 14 of 23 children with Primary IGFD treated for 2 years. However, no clinical consequences of these antibodies were observed (e.g., attenuation of growth). 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 Increlex® with the incidence of antibodies to other products may be misleading.

Post-Marketing Experience

The following adverse reactions have been identified during post approval use of Increlex®. 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; anaphylaxis, generalized urticaria, angioedema, dyspnea

In the post-marketing setting, the frequency of cases indicative of anaphylaxis was estimated to be 0.3%. Symptoms included hives, angioedema, and dyspnea, and some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

Local allergic reactions at the injection site; pruritis, urticaria.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. Studies to assess embryo-fetal toxicity evaluated the effects of Increlex® during organogenesis in Sprague Dawley rats given 1, 4, and 16 mg/kg/day and in New Zealand White rabbits given 0.125, 0.5, and 2 mg/kg/day, administered intravenously. There were no observed embryo-fetal developmental abnormalities in rats given up to 16 mg/kg/day (20 times the maximum recommended human dose [MRHD] based on body surface area [BSA] comparison). In the rabbit study, the NOAEL for fetal toxicity was 0.5 mg/kg (2 times the MRHD based on BSA) due to an increase in fetal death at 2 mg/kg. Increlex® displayed no teratogenicity or maternal toxicity in rabbits given up to 2 mg/kg (8 times the MRHD based on BSA).

The effects of Increlex® on an unborn child have not been studied. Therefore, there is insufficient medical information to determine whether there are significant risks to a fetus.

Nursing Mothers

Excretion of Increlex® in human milk has not been studied. As many drugs are excreted in human milk, caution should be exercised when Increlex® is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 years of age have not been established.

Geriatric Use

The safety and effectiveness of Increlex® in patients aged 65 and over has not been established.

Renal Impairment

No Studies have been conducted in Primary IGFD children or adult subjects with renal impairment [see Clinical Pharmacology (12.3)].

Hepatic Impairment

No studies have been conducted in Primary IGFD children or adult subjects with hepatic impairment [see Clinical Pharmacology (12.3)].

Overdosage

There is no clinical experience with overdosage of Increlex®. Based on known pharmacological effects, acute overdosage may lead to hypoglycemia. Long-term overdosage may result in signs and symptoms of acromegaly. Treatment of acute overdose of Increlex® should be directed at reversing hypoglycemia. Oral glucose or food should be consumed. If the overdose results in loss of consciousness, intravenous glucose or parenteral glucagon may be required to reverse the hypoglycemic effects.

Increlex Description

Increlex® (mecasermin [rDNA origin] injection) contains human insulin-like growth factor-1 (rhIGF-1) produced by recombinant DNA technology. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges and a molecular weight of 7649 daltons. The amino acid sequence of the product is identical to that of endogenous human IGF-1. The rhIGF-1 protein is synthesized in bacteria (E. coli) that have been modified by the addition of the gene for human IGF-1.

Increlex® is a sterile, aqueous, clear and colorless solution intended for subcutaneous injection. Each multi-dose vial of Increlex® contains 10 mg per mL mecasermin, 9 mg per mL benzyl alcohol, 5.84 mg per mL sodium chloride, 2 mg per mL polysorbate 20, and 0.05M acetate at a pH of approximately 5.4.

Increlex - Clinical Pharmacology

Mechanism of Action

Insulin-like growth factor-1 (IGF-1) is a key hormonal mediator on statural growth. Under normal circumstances, growth hormone (GH) binds to its receptor in the liver, and other tissues, and stimulates the synthesis/secretion of IGF-1. In target tissues, the Type 1 IGF-1 receptor, which is homologous to the insulin receptor, is activated by IGF-1, leading to intracellular signaling which stimulates multiple processes resulting in statural growth. The metabolic actions of IGF-1 are in part directed at stimulating the uptake of glucose, fatty acids, and amino acids so that metabolism supports growing tissues.

Pharmacodynamics

The following actions have been demonstrated for endogenous human IGF-1:

Tissue Growth – 1) Skeletal growth occurs at the cartilage growth plates of the epiphyses of bones where stem cells divide to produce new cartilage cells or chondrocytes. The growth of chondrocytes is under the control of IGF-1 and GH. The chondrocytes become calcified so that new bone is formed allowing the length of the bones to increase. This results in skeletal growth until the cartilage growth plates fuse at the end of puberty. 2) Cell growth: IGF-1 receptors are present on most types of cells and tissues. IGF-1 has mitogenic activities that lead to an increased number of cells in the body. 3) Organ growth: Treatment of IGF-1 deficient rats with rhIGF-1 results in whole body and organ growth.

Carbohydrate Metabolism –IGF-1 suppresses hepatic glucose production and stimulates peripheral glucose utilization and therefore has a hypoglycemic potential. IGF-1 has inhibitory effects on insulin secretion.

Pharmacokinetics

Absorption – The absolute bioavailability of rhIGF-1 after subcutaneous administration in healthy subjects is estimated to be close to 100%. However, the absolute bioavailability of Increlex® given subcutaneously to subjects with primary insulin-like growth factor-1 deficiency (Primary IGFD) has not been determined.

Distribution – In blood, IGF-1 is bound to six IGF binding proteins, with > 80% bound as a complex with IGFBP-3 and an acid-labile subunit. IGFBP-3 is greatly reduced in subjects with severe Primary IGFD, resulting in increased clearance of IGF-1 in these subjects relative to healthy subjects. The total IGF-1 volume of distribution after subcutaneous administration in subjects with severe Primary IGFD is estimated to be 0.257 (± 0.073) L/kg at an Increlex® dose of 0.045 mg/kg, and is estimated to increase as the dose of Increlex® increases.

Elimination – IGF-1 is metabolized by both liver and kidney. The mean terminal t1/2 after single subcutaneous administration of 0.12 mg/kg Increlex® in pediatric subjects with severe Primary IGFD is estimated to be 5.8 hours. Clearance of Increlex® is inversely proportional to IGF binding protein-3 (IGFBP-3) levels. CL/F is estimated to be 0.04 L/hr/kg at 0.5 micrograms/mL of IGFBP-3, and 0.01 L/hr/kg at 3 micrograms/mL IGFBP-3; the latter is the median IGFBP-3 in subjects with normal IGF-1 serum levels.

Gender – In children with Primary IGFD there were no apparent differences between males and females in the pharmacokinetics of Increlex®.

Race –The effect of race on pharmacokinetics of Increlex® has not been studied.

Summary of Increlex® Single-Dose Pharmacokinetic Parameters in Children with Severe Primary IGFD (0.12 mg/kg, SC)

	Cmax (ng/mL)	Tmax (hr)	AUC0-8 (hr*ng/mL)	t1/2 (hr)	Vd/F (L/kg)	CL/F (L/hr/kg)
n	3	3	3	3	12*	12*
Cmax = maximum concentration; Tmax = time of maximum concentration; AUC0-8 = area under the curve; t1/2 = half-life; Vd/F = apparent volume of distribution; CL/F = apparent systemic clearance; SC = subcutaneous injection; CV% = coefficient of variation in %.
Male/female data combined, ages 12 to 22 years.
PK parameters based on baseline adjusted plasma concentrations.
* Data represents 3 subjects each at doses 0.015, 0.03, 0.06, and 0.12 mg/kg SC.
Mean	234	2	2932	5.8	0.257	0.0424
CV%	23	0	50	64	28	38

Mean Total IGF-1 Concentration after a Single Subcutaneous Dose of Increlex® in Children with Severe Primary IGFD (0.06 mg/kg and 0.12 mg/kg, n = 3 per group)

Renal impairment– No studies have been conducted in Primary IGFD children with renal impairment.

Hepatic impairment– No studies have been conducted to determine the effect of hepatic impairment on the pharmacokinetics of rhIGF-1 in Primary IGFD children with hepatic impairment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: Increlex® was tumorigenic in rats in a study using doses of 0, 0.25, 1, 4, and 10 mg/kg/day by subcutaneous injection for up to 2 years. The incidence of adrenal medullary hyperplasia and pheochromocytoma increased in male rats given ≥1 mg/kg/day (≥ 1 times the clinical exposure with the maximum recommended human dose [MRHD] based on AUC) and in female rats at all dose levels (≥ 30% of the clinical exposure with the MRHD based on AUC). The incidence of keratoacanthoma in the skin increased in male rats given 4 and 10 mg/kg/day (≥ 4 times the MRHD). The incidence of mammary gland carcinoma in male rats increased in animals treated with 10 mg/kg/day (7 times the MRHD based on AUC). Only doses that exceeded the maximum tolerated dose (MTD) (based on excess mortality secondary to IGF-1 induced hypoglycemia) caused skin and mammary tumors.

Mutagenesis: Increlex® was not clastogenic in the in vitro chromosome aberration assay and the in vivo mouse micronucleus assay.

Impairment of fertility: Increlex® had no effects on fertility in rats using intravenous doses 0.25, 1, and 4 mg/day (up to 4 times the clinical exposure with the MRHD based on AUC.)

Clinical Studies

Effects of Increlex® Treatment in Children with Severe Primary Insulin-like Growth Factor-1 Deficiency (Primary IGFD)

Five clinical studies (four open-label and one double-blind, placebo-controlled), with subcutaneous doses of Increlex® generally ranging from 0.06 to 0.12 mg/kg (60 to 120 micrograms/kg) administered twice daily, were conducted in 71 pediatric subjects with severe Primary IGFD. Patients were enrolled in the trials on the basis of extreme short stature, slow growth rates, low IGF-1 serum concentrations, and normal growth hormone secretion. Data from these 5 clinical studies were pooled for a global efficacy and safety analysis. Baseline characteristics for the patients evaluated in the primary and secondary efficacy analyses were (mean, SD): chronological age (years): 6.7 ± 3.8; height (cm): 84.8 ± 15.3 cm; height standard deviation score (SDS): -6.7 ± 1.8; height velocity (cm/yr): 2.8 ± 1.8; height velocity SDS: -3.3 ± 1.7; IGF-1 (ng/mL): 21.6 ± 20.6; IGF-1 SDS: -4.3 ± 1.6; and bone age (years): 4.2 ± 2.8. Sixty-one subjects had at least one year of treatment. Fifty-three (87%) had Laron Syndrome; 7 (11%) had GH gene deletion, and 1 (2%) had neutralizing antibodies to GH. Thirty-seven (61%) of the subjects were male; forty-eight (79%) were Caucasian. Fifty-six (92%) of the subjects were pre-pubertal at baseline.

Annual results for height velocity, height velocity SDS, and height SDS are shown in Table 1. Pre-treatment height velocity data were available for 58 subjects. The height velocities at a given year of treatment were compared by paired t-tests to the pre-treatment height velocities of the same subjects completing that treatment year.

Table 1: Annual Height Results by Number of Years Treated with Increlex®

	Pre-Tx	Year 1	Year 2	Year 3	Year 4	Year 5	Year 6	Year 7	Year 8
Pre-Tx = Pre-treatment; SD = Standard Deviation; SDS = Standard Deviation Score
[1] P-values for comparison versus pre-treatment values are computed using paired t-tests.
Height Velocity (cm/yr)
N	58	58	48	38	23	21	20	16	13
Mean (SD)	2.8 (1.8)	8.0 (2.2)	5.8 (1.5)	5.5 (1.8)	4.7 (1.6)	4.7 (1.6)	4.8 (1.5)	4.6 (1.5)	4.3 (1.1)
Mean (SD) for change from pre-treatment		+5.2 (2.6)	+2.9 (2.4)	+2.3 (2.4)	+1.5 (2.2)	+1.5 (1.8)	+1.5 (1.7)	+1.0 (2.1)	+0.7 (2.5)
P-value for change from pre-treatment [1]		<0.0001	<0.0001	<0.0001	0.0045	0.0015	0.0009	0.0897	0.3059
Height Velocity SDS
N	58	58	47	37	22	19	18	15	11
Mean (SD)	-3.3 (1.7)	1.9 (3.0)	-0.2 (1.6)	-0.2 (2.0)	-0.7 (2.1)	-0.6 (2.1)	-0.4 (1.4)	-0.4 (1.9)	-0.4 (1.9)
Mean (SD) for change from pre-treatment		+5.2 (3.1)	+3.1 (2.3)	+2.9 (2.3)	+2.2 (2.2)	+2.5 (2.2)	+2.7 (1.7)	+2.5 (2.1)	+2.7 (2.8)
Height SDS
N	61	61	51	40	24	21	20	16	13
Mean (SD)	-6.7 (1.8)	-5.9 (1.8)	-5.6 (1.8)	-5.4 (1.8)	-5.5 (1.9)	-5.6 (1.8)	-5.4 (1.8)	-5.2 (2.0)	-5.2 (2.0)
Mean (SD) for change from pre-treatment		+0.8 (0.5)	+1.2 (0.8)	+1.4 (1.1)	+1.3 (1.2)	+1.4 (1.3)	+1.4 (1.2)	+1.4 (1.1)	+1.5 (1.1)

Forty-nine subjects were included in an analysis of the effects of Increlex® on bone age advancement. The mean ± SD change in chronological age was 4.9 ± 3.4 years and the mean ± SD change in bone age was 5.3 ± 3.4 years.

How Supplied/Storage and Handling

NDC-15054-1040-5

Increlex® is supplied as a 10 mg per mL sterile solution in multiple dose glass vials (40 mg per vial).

Before Opening – Vials of Increlex® are stable when refrigerated [2° to 8°C (35° to 46°F)]. Avoid freezing the vials of Increlex®. Protect from direct light. Expiration dates are stated on the labels.

After Opening – Vials of Increlex® are stable for 30 days after initial vial entry when stored at 2° to 8°C (35° to 46°F). Avoid freezing the vials of Increlex®. Protect from direct light.

Vial contents should be clear without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected. Increlex® should not be used after its expiration date. Keep refrigerated and use within 30 days of initial vial entry. Remaining unused material should be discarded.

Patient Counseling Information

Patients and/or their parents should be instructed in the safe administration of Increlex®. Increlex® should be given shortly before or after (20 minutes on either side of) a meal or snack. Increlex® should not be administered when the meal or snack is omitted. The dose of Increlex® should never be increased to make up for one or more omitted doses. Increlex® therapy should be initiated at a low dose and the dose should be increased only if no hypoglycemia episodes have occurred after at least 7 days of dosing. If severe hypoglycemia or persistent hypoglycemia occurs on treatment despite adequate food intake, Increlex® dose reduction should be considered. Providers should educate patients and caregivers on how to recognize the signs and symptoms of hypoglycemia.

Increlex® treatment may need to be discontinued if allergic reactions occur. Providers should educate patients and caregivers on the identification of signs and symptoms of serious allergic reactions to Increlex® and the need to seek prompt medical contact should such a reaction occur.

Patients and/or parents should be thoroughly instructed in the importance of proper needle disposal. A puncture-resistant container should be used for the disposal of used needles and/or syringes (consistent with applicable state requirements). Needles and syringes must not be reused.

Manufactured for:	Tercica, Inc. Brisbane, CA 94005 USA
by:	Hospira, Incorporated McPherson, KS 67460 USA

Patient Information

Increlex® (EENK-ruh-lex)

(mecasermin [rDNA origin] injection)

Read the Patient Information that comes with Increlex® before your child starts taking Increlex® and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your child's doctor about your child's condition or treatment.

What is Increlex®?

Increlex® is a liquid that contains man-made insulin-like growth factor-1 (IGF-1), which is the same as the IGF-1 made by your body. Increlex® is used to treat children who are very short for their age because their bodies do not make enough IGF-1. This condition is called primary IGF-1 deficiency. IGF-1 should not be used instead of growth hormone.

Increlex® has not been studied in children under 2 years of age.

Who Should Not Use Increlex®?

Your child should not take Increlex® if your child:

• Has finished growing (the bone growth plates are closed)


• Has cancer


• Has other causes of growth failure


• Is allergic to mecasermin or any of the inactive ingredients in Increlex®. Check with your child's doctor if you are not sure.

 

Your child should never receive Increlex® through a vein.

What should I tell my child's doctor before my child starts Increlex®?

Tell your child's doctor about all of your child's health conditions, including if your child:

• Has diabetes


• Has kidney problems


• Has liver problems


• Has a curved spine (scoliosis)


• Is pregnant or breast-feeding.

Tell your child's doctor about all the medicines your child takes, including prescription and nonprescription medicines, vitamins, and herbal supplements. Especially tell your child's doctor if your child takes insulin or other anti-diabetes medicines. A dose adjustment may be needed for these medicines.

How Should My Child Use Increlex®?

• Use Increlex® exactly as prescribed for your child. Your doctor or nurse should teach you how to inject Increlex®. Do not give your child Increlex® unless you understand all of the instructions. See the "Instructions for Use" at the end of this leaflet.


• Inject Increlex® under your child's skin shortly (20 minutes) before or after a meal or snack. Skip your child's dose of Increlex® if your child cannot eat for any reason. Do not make up the missed dose by giving two doses the next time.


• Inject Increlex® just below the skin in your child's upper arm, upper leg (thigh), stomach area (abdomen), or buttocks. Never inject it into a vein or muscle. Change the injection site for each injection ("rotate the injection site").


• Only use Increlex® that is clear and colorless. If your child's Increlex® is cloudy or slightly colored, return it for a replacement.

What are the Possible Side Effects of Increlex®?

Increlex® may cause the following side effects, which can be serious:

• Low blood sugar (hypoglycemia). Increlex® may lower blood sugar levels like insulin. It is important to only give your child Increlex® right before or right after (20 minutes on either side of) a snack or meal to reduce the chances of low blood sugar. Do not give your child Increlex® if your child is sick or cannot eat. Signs of low blood sugar are:
  
  • Dizziness
  
  
  • Tiredness
  
  
  • Restlessness
  
  
  • Hunger
  
  
  • Irritability
  
  
  • Trouble concentrating
  
  
  • Sweating
  
  
  • Nausea
  
  
  • Fast or irregular heartbeat
  
  

Severe hypoglycemia may cause unconsciousness, seizures, or death. If you take Increlex®, you should avoid participating in high risk activities (such as driving) within 2 to 3 hours after Increlex® injection, especially at the beginning of Increlex® treatment.

Before beginning treatment with Increlex® your doctor or nurse will explain to you how to treat hypoglycemia. You/your child should always have a source of sugar such as orange juice, glucose gel, candy, or milk available in case symptoms of hypoglycemia occur. For severe hypoglycemia, if your child is not responsive and cannot drink sugar-containing fluids, you should give an injection of glucagon. Your doctor or nurse will instruct you how to give the injection.

Glucagon raises the blood sugar when it is injected. It is important that your child have a well-balanced diet including protein and fat such as meat and cheese in addition to sugar-containing foods.

• Enlarged tonsils. Increlex® may enlarge your child's tonsils. Some signs of enlarged tonsils include: snoring, difficulty breathing or swallowing, sleep apnea (a condition where breathing stops briefly during sleep), or fluid in the middle-ear. Sleep apnea can cause excessive daytime sleepiness. Call your doctor should these symptoms bother your child. Your doctor should do regular exams to check your child's tonsils.


• Increased pressure in the brain (intracranial hypertension). Increlex®, like growth hormone, can sometimes cause a temporary increase in pressure within the brain. The symptoms of intracranial hypertension can include headache and nausea with vomiting. Tell your doctor if your child has headache with vomiting. Your doctor can then check to see if intracranial hypertension is present. If it is present, your doctor may decide to temporarily reduce or discontinue Increlex® therapy. Increlex® therapy may be started again after the episode is over.


• A bone problem called slipped capital femoral epiphysis. This happens when the top of the upper leg (femur) slips apart. Get medical attention for your child right away if your child develops a limp or has hip or knee pain.


• Worsened scoliosis (caused by rapid growth). If your child has scoliosis, your child will need to be checked often for an increase in the curve of the spine.


• Allergic reactions. Your child may have a mild or serious allergic reaction with Increlex®. Call your child's doctor right away if your child gets a rash or hives. Hives, also known as urticaria, appear as a raised, itchy skin reaction. Hives appear pale in the middle with a red rim around it. Hives generally appear minutes to hours after the injection and may sometimes occur at numerous places on the skin. Get medical help immediately if your child has trouble breathing or goes into shock, with symptoms like dizziness, pale, clammy skin and/or passing out.

Increlex® can cause reactions at the injection site including:

• Loss of fat (lipoatrophy)


• Increase of fat (lipohypertrophy)


• Pain, redness, or bruising

Injection site reactions can be avoided by changing the injection site at each injection ("injection site rotation").

Call your child's doctor if your child has side effects that are bothersome or that do not go away.

These are not all the side effects of Increlex®. Ask your child's doctor or pharmacist for more information.

How Should I Store Increlex®?

• Before Opening – Store new unopened vials of Increlex® in the refrigerator (not the freezer) between 35° to 46°F (2° to 8°C). Do not freeze Increlex®. Keep Increlex® out of direct heat and bright light. If a vial freezes, throw it away.


• After Opening – Once a vial of Increlex® is opened, you can keep it in the refrigerator between 35° to 46°F (2° to 8°C) for 30 days after you start using the vial. Do not freeze Increlex®. Keep Increlex® out of direct heat and bright light. If a vial freezes, throw it away.

Keep Increlex® and all medicines out of reach of children.

General Information About Increlex®

Medicines are sometimes prescribed for conditions other than those described in patient information leaflets. Do not give Increlex® to your child for a condition for which it was not prescribed. Do not give Increlex® to a person other than your child. It may be harmful.

This leaflet summarizes the most important information about Increlex®. If you would like more information, talk to your child's doctor. You can also ask your child's doctor or pharmacist for information that is written for health professionals.

More information is available at 1-866-TERCICA (1-866-837-2422).

What are the Ingredients in Increlex®?

Active ingredient: mecasermin

Inactive ingredients: sodium chloride, polysorbate 20, benzyl alcohol, and acetate.

INSTRUCTIONS FOR USE

Increlex® should be administered using sterile disposable syringes and needles. The syringes should be of small enough volume that the prescribed dose can be withdrawn from the vial with reasonable accuracy.

Preparing the Dose:

1. Wash your hands before getting Increlex® ready for your child's injection.


2. Use a new disposable needle and syringe every time you give a dose. Use syringes and needles only once. Throw them away properly. Never share needles and syringes.


3. Check the liquid to make sure it is clear and colorless. Do not use after the expiration date or if it is cloudy or if you see particles.


4. If you are using a new vial, remove the protective cap. Do not remove the rubber stopper.


5. Wipe the rubber stopper of the vial with an alcohol swab to prevent contamination of the vial by germs that may be introduced by repeated needle insertions (see Figure 1).