Actimmune

interferon gamma-1b

Dosage Form: injection, solution
Actimmune® (Interferon gamma-1b)

Actimmune Description

Actimmune®  (Interferon gamma-1b), a biologic response modifier, is a single-chain polypeptide containing 140 amino acids. Production of Actimmune  is achieved by fermentation of a genetically engineered Escherichia coli  bacterium containing the DNA which encodes for the human protein. Purification of the product is achieved by conventional column chromatography. Actimmune  is a highly purified sterile solution consisting of non-covalent dimers of two identical 16,465 dalton monomers; with a specific activity of 20 million International Units (IU)/mg (2x106 IU per 0.5 mL) which is equivalent to 30 million units/mg.

Actimmune  is a sterile, clear, colorless solution filled in a single-use vial for subcutaneous injection. Each 0.5 mL of Actimmune  contains: 100 mcg (2 million IU) of Interferon gamma-1b formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 and Sterile Water for Injection. Note that the above activity is expressed in International Units (1 million IU/50mcg). This is equivalent to what was previously expressed as units (1.5 million U/50mcg).

Actimmune - Clinical Pharmacology

General

Interferons bind to specific cell surface receptors and initiate a sequence of intracellular events that lead to the transcription of interferon-stimulated genes. The three major groups of interferons (alpha, beta, gamma) have partially overlapping biological activities that include immunoregulation such as increased resistance to microbial pathogens and inhibition of cell proliferation. Type 1 interferons (alpha and beta) bind to the alpha/beta receptor. Interferon-gamma binds to a different cell surface receptor and is classified as Type 2 interferon. Specific effects of interferon-gamma include the enhancement of the oxidative metabolism of macrophages, antibody dependent cellular cytotoxicity (ADCC), activation of natural killer (NK) cells, and the expression of Fc receptors and major histocompatibility antigens.

Chronic Granulomatous Disease (CGD) is an inherited disorder of leukocyte function caused by defects in the enzyme complex responsible for phagocyte superoxide generation. Actimmune  does not increase phagocyte superoxide production even in treatment responders.1

In severe, malignant osteopetrosis (an inherited disorder characterized by an osteoclast defect, leading to bone overgrowth, and by deficient phagocyte oxidative metabolism), a treatment-related enhancement of superoxide production by phagocytes was observed. Actimmune  was found to enhance osteoclast function in vivo.2-4

In both disorders, the exact mechanism(s) by which Actimmune  has a treatment effect has not been established. Changes in superoxide levels during Actimmune  therapy do not predict efficacy and should not be used to assess patient response to therapy.

Pharmacokinetics

The intravenous, intramuscular, and subcutaneous pharmacokinetics of Actimmune  have been investigated in 24 healthy male subjects following single-dose administration of 100 mcg/m2. Actimmune  is rapidly cleared after intravenous administration (1.4 liters/minute) and slowly absorbed after intramuscular or subcutaneous injection. After intramuscular or subcutaneous injection, the apparent fraction of dose absorbed was greater than 89%. The mean elimination half-life after intravenous administration of 100 mcg/m2 in healthy male subjects was 38 minutes. The mean elimination half-lives for intramuscular and subcutaneous dosing with 100 mcg/m2 were 2.9 and 5.9 hours, respectively. Peak plasma concentrations, determined by ELISA, occurred approximately 4 hours (1.5 ng/mL) after intramuscular dosing and 7 hours (0.6 ng/mL) after subcutaneous dosing. Multiple dose subcutaneous pharmacokinetic studies were conducted in 38 healthy male subjects. There was no accumulation of Actimmune  after 12 consecutive daily injections of 100 mcg/m2. Pharmacokinetic studies in patients with Chronic Granulomatous Disease have not been performed.

Trace amounts of interferon-gamma were detected in the urine of squirrel monkeys following intravenous administration of 500 mcg/kg. Interferon-gamma was not detected in the urine of healthy human volunteers following administration of 100 mcg/m2 of Actimmune  by the intravenous, intramuscular and subcutaneous routes. In vitro  perfusion studies utilizing rabbit livers and kidneys demonstrate that these organs are capable of clearing interferon-gamma from perfusate. Studies of the administration of interferon-gamma to nephrectomized mice and squirrel monkeys demonstrate a reduction in clearance of interferon-gamma from blood; however, prior nephrectomy did not prevent elimination.

Effects in Chronic Granulomatous Disease

A randomized, double-blind, placebo-controlled study of Actimmune  (Interferon gamma-1b) in patients with Chronic Granulomatous Disease (CGD), was performed to determine whether Actimmune  administered subcutaneously on a three times weekly schedule could decrease the incidence of serious infectious episodes and improve existing infectious and inflammatory conditions in patients with Chronic Granulomatous Disease. One hundred twenty-eight eligible patients were enrolled on this study including patients with different patterns of inheritance. Most patients received prophylactic antibiotics. Patients ranged in age from 1 to 44 years with the mean age being 14.6 years. The study was terminated early following demonstration of a highly statistically significant benefit of Actimmune  therapy compared to placebo with respect to time to serious infection (p=0.0036), the primary endpoint of the investigation. Serious infection was defined as a clinical event requiring hospitalization and the use of parenteral antibiotics. The final analysis provided further support for the primary endpoint (p=0.0006). There was a 67 percent reduction in relative risk of serious infection in patients receiving Actimmune  (n=63) compared to placebo (n=65). Additional supportive evidence in the number of primary serious infections in the Actimmune  group (30 on placebo versus 14 on Actimmune, p=0.002) and the total number and rate of serious infections including recurrent events (56 on placebo versus 20 on Actimmune, p=<0.0001). Moreover, the length of hospitalization for the treatment of all clinical events provided evidence highly supportive of an Actimmune  treatment benefit. Placebo patients required three times as many inpatient hospitalization days for treatment of clinical events compared to patients receiving Actimmune  (1493 versus 497 total days, p=0.02). An Actimmune  treatment benefit with respect to time to serious infection was consistently demonstrated in all subgroup analyses according to stratification factors, including pattern of inheritance, use of prophylactic antibiotics, as well as age. There was a 67 percent reduction in relative risk of serious infection in patients receiving Actimmune  compared to placebo across all groups. The beneficial effect of Actimmune  therapy was observed throughout the entire study, in which the mean duration of Actimmune  administration was 8.9 months/patient.

Effects in Osteopetrosis

A controlled, randomized study in patients with severe, malignant osteopetrosis was conducted with Actimmune  administered subcutaneously three times weekly. Sixteen patients were randomized to receive either Actimmune  plus calcitriol (n=11), or calcitriol alone (n=5). Patients ranged in age from 1 month to 8 years, mean 1.5 years. Treatment failure was considered to be disease progression as defined by 1) death, 2) significant reduction in hemoglobin or platelet counts, 3) a serious bacterial infection requiring antibiotics, or 4) a 50 dB decrease in hearing or progressive optic atrophy. The median time to disease progression was significantly delayed in the Actimmune  plus calcitriol arm versus calcitriol alone. In the treatment arm, the median was not reached. Based on the observed data, however, the median time to progression in this arm was at least 165 days versus a median of 65 days in the calcitriol alone arm. In an analysis which combined data from a second study, 19 of 24 patients treated with Actimmune  plus or minus calcitriol for at least 6 months had reduced trabecular bone volume compared to baseline.

Indications and Usage for Actimmune

Actimmune  is indicated for reducing the frequency and severity of serious infections associated with Chronic Granulomatous Disease.

Actimmune  is indicated for delaying time to disease progression in patients with severe, malignant osteopetrosis.

Contraindications

Actimmune  is contraindicated in patients who develop or have known hypersensitivity to interferon-gamma, E. coli  derived products, or any component of the product.

Warnings

Cardiovascular Disorders

Acute and transient "flu-like" symptoms such as fever and chills induced by Actimmune  at doses of 250 mcg/m2/day (greater than 10 times the weekly recommended dose) or higher may exacerbate pre-existing cardiac conditions. Actimmune  should be used with caution in patients with pre-existing cardiac conditions, including ischemia, congestive heart failure or arrhythmia.

Neurologic Disorders

Decreased mental status, gait disturbance and dizziness have been observed, particularly in patients receiving Actimmune  doses greater than 250 mcg/m2/day (greater than 10 times the weekly recommended dose). Most of these abnormalities were mild and reversible within a few days upon dose reduction or discontinuation of therapy. Caution should be exercised when administering Actimmune  to patients with seizure disorders or compromised central nervous system function.

Bone Marrow Toxicity

Reversible neutropenia and thrombocytopenia that can be severe and may be dose related have been observed during Actimmune  therapy. Caution should be exercised when administering Actimmune  to patients with myelosuppression.

Hepatic Toxicity

Elevations of AST and/or ALT (up to 25-fold) have been observed during Actimmune  therapy. The incidence appeared to be higher in patients less than 1 year of age compared to older children. The transaminase elevations were reversible with reduction in dosage or interruption of Actimmune  treatment. Patients begun on Actimmune  before age one year should receive monthly assessments of liver function. If severe hepatic enzyme elevations develop, Actimmune  dosage should be modified (see DOSAGE AND ADMINISTRATION: Dose Modification).

Precautions

General

Isolated cases of acute serious hypersensitivity reactions have been observed in patients receiving Actimmune. If such an acute reaction develops the drug should be discontinued immediately and appropriate medical therapy instituted. Transient cutaneous rashes have occurred in some patients following injection but have rarely necessitated treatment interruption.

Information for Patients

Patients being treated with Actimmune  and/or their parents should be informed regarding the potential benefits and risks associated with treatment. If home use is determined to be desirable by the physician, instructions on appropriate use should be given, including review of the contents of the Patient Information Insert. This information is intended to aid in the safe and effective use of the medication. It is not a disclosure of all possible adverse or intended effects.

If home use is prescribed, a puncture resistant container for the disposal of used syringes and needles should be supplied to the patient. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of needles and syringes. The full container should be disposed of according to the directions provided by the physician (see Patient Information Insert).

The most common adverse experiences occurring with Actimmune  therapy are "flu-like" or constitutional symptoms such as fever, headache, chills, myalgia or fatigue (see ADVERSE REACTIONS) which may decrease in severity as treatment continues. Some of the "flu-like" symptoms may be minimized by bedtime administration. Acetaminophen may be used to prevent or partially alleviate the fever and headache.

Laboratory Tests

In addition to those tests normally required for monitoring patients with Chronic Granulomatous Disease and osteopetrosis, the following laboratory tests are recommended for all patients on Actimmune  (Interferon gamma-1b) therapy prior to the beginning of and at three month intervals during treatment (see WARNINGS: Bone Marrow and Hepatic Toxicity).

• Hematologic tests - including complete blood counts, differential and platelet counts


• Blood chemistries - including renal and liver function tests. In patients less than 1 year of age, liver function tests should be measured monthly (see ADVERSE REACTIONS: Post-Marketing Experience).


• Urinalysis

Drug Interactions

Interactions between Actimmune and other drugs have not been fully evaluated. Caution should be exercised when administering Actimmune  in combination with other potentially myelosuppressive agents (see WARNINGS).

Preclinical studies in rodents using species-specific interferon-gamma have demonstrated a decrease in hepatic microsomal cytochrome P-450 concentrations. This could potentially lead to a depression of the hepatic metabolism of certain drugs that utilize this degradative pathway.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Carcinogenesis: Actimmune  has not been tested for its carcinogenic potential.

Mutagenesis:  Ames tests using five different tester strains of bacteria with and without metabolic activation revealed no evidence of mutagenic potential. Actimmune  was tested in a micronucleus assay for its ability to induce chromosomal damage in bone marrow cells of mice following two intravenous doses of 20 mg/kg. No evidence of chromosomal damage was noted.

Impairment of Fertility:  Female cynomolgus monkeys treated with daily subcutaneous doses of 30 or 150 mcg/kg Actimmune  (approximately 20 and 100 times the human dose) exhibited irregular menstrual cycles or absence of cyclicity during treatment. Similar findings were not observed in animals treated with 3 mcg/kg Actimmune.

Female mice receiving recombinant murine IFN-gamma (rmulFN-gamma) at 32 times the maximum recommended clinical dose of Actimmune  for 4 weeks via intramuscular injection exhibited an increased incidence of atretic ovarian follicles.

Male cynomolgus monkeys treated intravenously for 4 weeks with 8 times the maximum recommended clinical dose of Actimmune  exhibited decreased spermatogenesis. The impact of this finding on fertility is not known. Male mice receiving rmulFN-gamma at 32 times the maximum recommended clinical dose of Actimmune  for 4 weeks via intramuscular injection exhibited decreased spermatogenesis.

Male mice treated subcutaneously with rmuIFN-gamma from shortly after birth through puberty, with 280 times the maximum recommended clinical dose of Actimmune  exhibited profound yet reversible decreases in sperm counts and fertility, and an increase in the number of abnormal sperm.

The clinical significance of these findings observed following treatment of mice with rmulFN-gamma is uncertain.

Pregnancy

Teratogenic Effects:  Pregnancy Category C. Actimmune  has shown an increased incidence of abortions in primates when given in doses approximately 100 times the human dose. A study in pregnant primates treated with subcutaneous doses 2-100 times the human dose failed to demonstrate teratogenic activity for Actimmune.

Female mice treated subcutaneously with rmulFN-gamma at 280 times the maximum recommended clinical dose of Actimmune  from shortly after birth through puberty but not during pregnancy had offspring which exhibited decreased body weight during the lactation period. The clinical significance of this finding observed following treatment of mice with rmulFN-gamma is uncertain.

There are no adequate and well-controlled studies in pregnant women. Actimmune  should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

It is not known whether Actimmune  is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Actimmune, a decision should be made whether to discontinue nursing or to discontinue the drug, dependent upon the importance of the drug to the mother.

Adverse Reactions

The following data on adverse reactions are based on the subcutaneous administration of Actimmune  at a dose of 50 mcg/m2, three times weekly, in patients with Chronic Granulomatous Disease (CGD) during an investigational trial in the United States and Europe.

The most common adverse events observed in patients with CGD are shown in the following table:

		Percent of Patients
Clinical Toxicity		Actimmune CGD (n=63)		Placebo CGD (n=65)
Fever		52		28
Headache		33		9
Rash		17		6
Chills		14		0
Injection site erythema or tenderness		14		2
Fatigue		14		11
Diarrhea		14		12
Vomiting		13		5
Nausea		10		2
Myalgia		6		0
Arthralgia		2		0
Injection site pain		0		2

Miscellaneous adverse events which occurred infrequently in patients with CGD and may have been related to underlying disease included back pain (2 percent versus 0 percent), abdominal pain (8 percent versus 3 percent) and depression (3 percent versus 0 percent) for Actimmune  and placebo treated patients, respectively.

Similar safety data were observed in 34 patients with severe malignant osteopetrosis.

Actimmune  has also been evaluated in additional disease states in studies in which patients have generally received higher doses (>100 mcg/m2/three times weekly) administered by intramuscular or subcutaneous injection, or intravenous infusion. All of the previously described adverse reactions which occurred in patients with Chronic Granulomatous Disease have also been observed in patients receiving higher doses. Adverse reactions not observed in patients with Chronic Granulomatous Disease but reported in patients receiving Actimmune  (Interferon gamma-1b) in other studies include: Cardiovascular—hypotension, syncope, tachyarrhythmia, heart block, heart failure, and myocardial infarction. Central Nervous System—confusion, disorientation, gait disturbance, Parkinsonian symptoms, seizure, hallucinations, and transient ischemic attacks. Gastrointestinal—dyspepsia, hepatic insufficiency, gastrointestinal bleeding, and pancreatitis, including pancreatitis with fatal outcome. General Disorders and Administration Site Conditions—malaise, injection site hemorrhage. Hematologic—deep venous thrombosis and pulmonary embolism. Immunological—increased autoantibodies, lupus-like syndrome. Metabolic—hyponatremia, hyperglycemia and hypertriglyceridemia. Musculoskeletal—clubbing, muscle spasms. Pulmonary—tachypnea, bronchospasm, and interstitial pneumonitis. Renal—reversible renal insufficiency. Other—chest discomfort, exacerbation of dermatomyositis.

Abnormal Laboratory Test Values:  Elevations of ALT and AST, neutropenia, thrombocytopenia, and proteinuria have been observed (see WARNINGS and PRECAUTIONS: Laboratory Tests).

No neutralizing antibodies to Actimmune  have been detected in any Chronic Granulomatous Disease patients receiving Actimmune.

Post-Marketing Experience

Children with CGD less than 3 years of age:

Data on the safety and activity of Actimmune  in 37 patients under the age of 3 years was pooled from four uncontrolled post-marketing studies. The rate of serious infections per patient-year in this uncontrolled group was similar to the rate observed in the Actimmune  treatment groups in controlled trials. Developmental parameters (height, weight and endocrine maturation) for this uncontrolled group conformed to national normative scales before and during Actimmune  therapy.

In 6 of the 10 patients receiving Actimmune  therapy before age one year 2-fold to 25-fold elevations from baseline of AST and/or ALT were observed. These elevations occurred as early as 7 days after starting treatment. Treatment with Actimmune  was interrupted in all 6 of these patients and was restarted at a reduced dosage in 4. Liver transaminase values returned to baseline in all patients and transaminase elevation recurred in one patient upon Actimmune  rechallenge. An 11-fold alkaline phosphatase elevation and hypokalemia in one patient and neutropenia (ANC=525 cells/mm3) in another patient resolved with interruption of Actimmune  treatment and did not recur with rechallenge.

In the post-marketing safety database clinically significant adverse events observed during Actimmune  therapy in children under the age of three years (n=14) included: two cases of hepatomegaly, and one case each of Stevens-Johnson syndrome, granulomatous colitis, urticaria, and atopic dermatitis.

Overdosage

Central nervous system adverse reactions including decreased mental status, gait disturbance and dizziness have been observed, particularly in cancer patients receiving doses greater than 100 mcg/m2/day by intravenous or intramuscular administration. These abnormalities were reversible within a few days upon dose reduction or discontinuation of therapy. Reversible neutropenia, elevation of hepatic enzymes and of triglycerides, and thrombocytopenia have also been observed.

Actimmune Dosage and Administration

The recommended dosage of Actimmune  for the treatment of patients with Chronic Granulomatous Disease and severe, malignant osteopetrosis is 50 mcg/m2 (1 million IU/m2) for patients whose body surface area is greater than 0.5 m2 and 1.5 mcg/kg/dose for patients whose body surface area is equal to or less than 0.5 m2. Note that the above activity is expressed in International Units (1 million IU/50mcg). This is equivalent to what was previously expressed as units (1.5 million U/50mcg). Injections should be administered subcutaneously three times weekly (for example, Monday, Wednesday, Friday). The optimum sites of injection are the right and left deltoid and anterior thigh. Actimmune  can be administered by a physician, nurse, family member or patient when trained in the administration of subcutaneous injections. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

The formulation does not contain a preservative. A vial of Actimmune  is suitable for a single use only. The unused portion of any vial should be discarded. Higher doses are not recommended. Safety and efficacy has not been established for Actimmune  given in doses greater or less than the recommended dose of 50 mcg/m2. The minimum effective dose of Actimmune  has not been established.

Actimmune  should not be mixed with other drugs in the same syringe.

Dose Modification

If severe reactions occur, the dosage should be reduced by 50 percent or therapy should be interrupted until the adverse reaction abates.

Actimmune  may be administered using either sterilized glass or plastic disposable syringes.

How is Actimmune Supplied

Actimmune  (Interferon gamma-1b) is a sterile, clear, colorless solution filled in a single-use vial for subcutaneous injection. Each 0.5 mL of Actimmune  contains: 100 mcg (2 million IU) of Interferon gamma-1b, formulated in 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate 20 and Sterile Water for Injection.

Single vial (NDC 64116-011-01)

Cartons of 12 (NDC 64116-011-12)

Stability and Storage

Vials of Actimmune  must be placed in a 2-8°C (36-46°F) refrigerator immediately upon receipt to ensure optimal retention of physical and biochemical integrity. DO NOT FREEZE. Avoid excessive or vigorous agitation. DO NOT SHAKE. An unentered vial of Actimmune  should not be left at room temperature for a total time exceeding 12 hours prior to use. Vials exceeding this time period should not be returned to the refrigerator; such vials should be discarded.

Do not use beyond the expiration date stamped on the vial.

REFERENCES

1. The International Chronic Granulomatous Disease Cooperative Study Group. A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. N Engl J Med 324 : 509-516, 1991.


2. Beard CJ, Key L, Newburger PE, Ezekowitz RAB, et al.  Neutrophil defect associated with malignant infantile osteopetrosis. J Lab Clin Med 108 : 498-505, 1986.


3. Shankar L, Gerritsen EJA, and Key LL. Osteopetrosis: pathogenesis and rationale for the use of interferon-γ-1b. Biodrugs 7 : 23-29, 1997.


4. Key LL, Rodriguiz RM, Willi SM. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med 24 : 1594-1599, 1995.

Manufactured by:

InterMune, Inc.

Brisbane, CA 94005

U.S. License No. 1626

Revised January 2009

©2009 InterMune, Inc.                           PH01037.04

Information for the Patient/Caregiver

Actimmune® (Interferon gamma-1b)

DO NOT ADMINISTER Actimmune  UNTIL YOUR PHYSICIAN HAS THOROUGHLY TRAINED YOU IN THE PROPER TECHNIQUES.

Actimmune  is supplied in single-use vials. The unused portion of each vial should be disposed of as instructed by your physician. DO NOT SHAKE.

Your physician will tell you what size needle and syringe to use and also give you instructions on sterile technique. Keep all used syringes and needles out of the reach of children. Follow your physician’s instructions on the safe disposal of used syringes and needles.

MEASURING THE DOSE

In measuring the correct dose for injection, be sure to check that the Actimmune®  solution is clear. If the solution is cloudy or hazy, do not inject it, but return the Actimmune  vial to your pharmacist or prescribing physician.

1.  Wash your hands thoroughly with soap and water before preparing the medication. This helps prevent infection.

2.  Check the date on the Actimmune  vial to be sure the drug has not expired.

3.  Remove the protective plastic cap and wipe the rubber stopper located on top of the Actimmune®  vial with an alcohol swab.

4.  Draw air into the syringe by pulling back on the plunger. The amount of air should be equal to the Actimmune  dose.

5.  Remove and save the needle guard. Slowly insert the needle straight through the center of the rubber stopper into the Actimmune  vial.

6.  Gently push the plunger to discharge the air into the vial.

7.  Turn the vial upside down with the syringe needle still in it and hold it in one hand. Be sure the tip of the needle is in the solution. Using your other hand slowly pull back on the plunger in a continuous motion until the correct amount of Actimmune®  solution is in the syringe.

8.  Remove the needle from the Actimmune  vial and replace the needle guard until time of administration or injection. Administration should be as soon after filling the syringe as possible; do not store Actimmune  in the syringe.

SELECTING THE INJECTION SITE

Your doctor or nurse will teach you how to locate appropriate injection sites. It is very important that you rotate the site of an injection each time you give the medication. Even if you or your child develop a preference for one site—as often happens—you still should rotate the injection site.

Following are the injection sites most often recommended:

■   Upper Arm

■   Abdomen

■   Thigh

GIVING THE MEDICATION

Your doctor or nurse will provide you with hands-on training on how to give an injection. Needles and syringes should be used only once to ensure sterility of both the needle and the syringe. The following is a review of the steps involved in giving the medication:

1.  Cleanse the injection site with an alcohol-saturated cotton ball or cotton swab.

2.  Remove the needle guard from the syringe filled with the proper dose of solution and hold the syringe the way you would hold a pencil. Double check that the correct amount of Actimmune®  solution is in the syringe.

3.  Squeeze the skin between your fingers before and during the injection. Insert the needle into the skin at a 45° angle with a quick, firm motion. This hurts less than pushing the needle in slowly.

4.  After the needle is in, pull back very slightly with one hand on the plunger to see if blood comes into the syringe. This is to be sure that the needle has not entered a blood vessel. If blood does come into the syringe, do not inject the Actimmune®  solution. Withdraw the needle and insert at another location.

5.  If blood does not come into the syringe, slowly (within a few seconds) inject the solution by gently pushing the plunger until the syringe is empty.

6.  Withdraw the needle quickly, pulling it straight out, and apply pressure over the injection site with a dry gauze pad or cotton ball. A drop of blood may appear. Put a Band-Aid® on the injection site if desired.

7.  To prevent injury, safely dispose of all used needles and syringes after a single use as instructed by your physician by following these simple steps:

■

Place all used needles and syringes in a hard, plastic container with a screw-on cap, or a metal container with a plastic lid, such as a coffee can properly labeled as to content. If a metal container is used, cut a small hole in the plastic lid and tape the lid to the metal container. When the metal container is full, cover the hole with tape and throw it away. If a hard, plastic container is used, always screw the cap on tightly after each use. When the plastic container is full, tape around the cap and throw it away.

■

Do not use glass or clear, plastic containers, or any container that will be recycled or returned to a store.

■

Always store the container out of the reach of children.

■

Please check with your doctor, nurse or pharmacist for other suggestions. There may be special state and local laws that they will discuss with you.

8.  Occasionally a problem may develop at the injection site. If you notice any of the following signs or symptoms, contact your doctor or nurse:

■

A lump or swelling that doesn’t go away

■

Bruising that doesn’t go away

■

Any signs of infection or inflammation at an injection site (pus, persistent redness, surrounding skin that is hot to the touch, persistent pain after the injection)

STORAGE

Actimmune®  (Interferon gamma-1b) must be refrigerated immediately. Refrigerate at 36° to 46° Fahrenheit (2° to 8° Centigrade). DO NOT FREEZE.

Actimmune  is supplied in single-use vials. The unused portion of each vial should be disposed of according to state and local regulations as instructed by your physician. If you have any questions, contact your physician.

InterMune, Inc.

Brisbane, CA 94005

PA01022.01

November 2006

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – VIAL

NDC 64116-011-01

Actimmune®

(Interferon gamma-1b)

100 mcg (2 million IU)/0.5 mL

0.5 mL Single-use vial

US License No.: 1626

Manufactured by:

Intermune, Inc.

Brisbane, CA 94005

DOSAGE AND ADMINISTRATION:

See package insert.

DO NOT SHAKE.

STORAGE:

Refrigerate at

2° to 8°C/

36° to 46°F.

DO NOT FREEZE.

Rx ONLY

LB0161.6

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – CARTON

KEEP REFRIGERATED

NDC 64116-011-12

Actimmune®

(Interferon gamma-1b)

How supplied: Each carton contains 12 single-use

vials of Interferon gamma-1b, Actimmune.

Contents: Each 0.5 mL vial of Actimmune

contains 100 mcg (2 million IU) Interferon

gamma-1b formulated in 20 mg mannitol, 0.36 mg

sodium succinate, 0.05 mg polysorbate 20 and

Sterile Water for Injection for subcutaneous

injection. Actimmune  contains no preservatives.

Dosage and administration: See

package insert for full prescribing

information. Actimmune  is

suitable for single-use only.

DO NOT SHAKE.

Storage: Refrigerate at

2° to 8°C/36° to 46°F.

DO NOT FREEZE.

Actimmune®

(Interferon gamma-1b)

Manufactured by:

Intermune, Inc.

Brisbane, CA 94005

US License No.: 1626

INTERMUNE®

KEEP REFRIGERATED

Actimmune®

(Interferon gamma-1b)

Dispensing pharmacist:

1. Refrigerate

    (2° to 8°C/36° to 46°F).

2. Be sure patient information

    is enclosed.

3. Remove physician insert

    before dispensing.

Rx ONLY

KEEP REFRIGERATED

INTERMUNE®

Actimmune  interferon gamma-1b  injection, solution

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 64116-011 Route of Administration SUBCUTANEOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Interferon gamma-1b (Interferon gamma-1b) Interferon gamma-1b 100 ug  in 0.5 mL

Inactive Ingredients Ingredient Name Strength mannitol 20 mg  in 0.5 mL sodium succinate 0.36 mg  in 0.5 mL polysorbate 20 0.05 mg  in 0.5 mL water

Product Characteristics Color      Score      Shape Size Flavor Imprint Code Contains

Packaging # NDC Package Description Multilevel Packaging 1 64116-011-12 12 VIAL In 1 CARTON contains a VIAL, SINGLE-USE (64116-011-01) 1 64116-011-01 0.5 mL In 1 VIAL, SINGLE-USE This package is contained within the CARTON (64116-011-12)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA103836	02/25/1999

Labeler - InterMune, Inc. (035491294)

Registrant - InterMune, Inc. (035491294)

Establishment
Name	Address	ID/FEI	Operations
Boehringer Ingelheim Pharma GmbH & Co KG		340700520	MANUFACTURE

Revised: 04/2011InterMune, Inc.

More Actimmune resources

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

• Actimmune Concise Consumer Information (Cerner Multum)


• Actimmune MedFacts Consumer Leaflet (Wolters Kluwer)


• Actimmune Monograph (AHFS DI)


• Actimmune Advanced Consumer (Micromedex) - Includes Dosage Information


• Interferon Gamma-1b Professional Patient Advice (Wolters Kluwer)

Compare Actimmune with other medications

• Chronic Granulomatous Disease
• Cutaneous T-cell Lymphoma
• Idiopathic Pulmonary Fibrosis
• Osteopetrosis

Symbicort Turbohaler 400 / 12, Inhalation powder.

Symbicort Turbohaler
400/12, inhalation powder

budesonide, formoterol fumarate dihydrate

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

In this leaflet:

• 1. What Symbicort Turbohaler is and what it is used for


• 2. Before you use Symbicort Turbohaler


• 3. How to use Symbicort Turbohaler


• 4. Possible side effects


• 5. How to store Symbicort Turbohaler


• 6. Further information

What Symbicort Turbohaler is and what it is used for

Symbicort Turbohaler is an inhaler. It contains two different medicines: budesonide and formoterol fumarate dihydrate.

• Budesonide belongs to a group of medicines called ‘corticosteroids’. It works by reducing and preventing swelling and inflammation in your lungs.


• Formoterol fumarate dihydrate belongs to a group of medicines called ‘long-acting beta-agonists’ or ‘bronchodilators’. It works by relaxing the muscles in your airways. This helps you to breathe more easily.

Your doctor has prescribed this medicine to treat asthma or chronic obstructive pulmonary disease (COPD).

Asthma

For asthma, your doctor will prescribe two asthma inhalers: Symbicort Turbohaler and a separate ‘reliever inhaler’.

• Use Symbicort Turbohaler every day. This helps to prevent asthma symptoms from happening.


• Use your ‘reliever inhaler’ when you get asthma symptoms, to make it easier to breathe again.

Do not use Symbicort Turbohaler 400/12 as a ‘reliever inhaler’.

Chronic obstructive pulmonary disease (COPD)

Symbicort Turbohaler can also be used to treat the symptoms of severe COPD in adults. COPD is a long-term disease of the airways in the lungs, which is often caused by cigarette smoking.

Before you use Symbicort Turbohaler

Do not use Symbicort Turbohaler if:

• You are allergic (hypersensitive) to budesonide, formoterol, or the other ingredient, which is lactose (which contains small amounts of milk proteins).

Take special care with Symbicort Turbohaler

Before you use Symbicort Turbohaler, tell your doctor or pharmacist if:

• You are diabetic.


• You have a lung infection.


• You have high blood pressure or you have ever had a heart problem (including an uneven heart beat, a very fast pulse, narrowing of the arteries or heart failure).


• You have problems with your thyroid or adrenal glands.


• You have low levels of potassium in your blood.


• You have severe liver problems.

Taking other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This includes medicines that you buy without a prescription and herbal medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

• Beta-blocker medicines (such as atenolol or propranolol for high blood pressure), including eyedrops (such as timolol for glaucoma).


• Medicines for a fast or uneven heart beat (such as quinidine).


• Medicines like digoxin, often used to treat heart failure.


• Diuretics, also known as ‘water tablets’ (such as furosemide). These are used to treat high blood pressure.


• Steroid medicines that you take by mouth (such as prednisolone).


• Xanthine medicines (such as theophylline or aminophylline). These are often used to treat asthma.


• Other bronchodilators (such as salbutamol).


• Tricyclic anti-depressants (such as amitriptyline).


• Mono-Amine Oxidase Inhibitors, also known as MAOIs (such as phenelzine).


• Phenothiazine medicines (such as chlorpromazine and prochlorperazine).


• Medicines called ‘protease inhibitors’ (such as ritonavir) to treat HIV infection.


• Medicines to treat fungal infections (such as itraconazole and ketoconazole).


• Medicines for Parkinson’s disease (such as leva-dopa).


• Medicines for thyroid problems (such as levo-thyroxine).

If any of the above applies to you, or if you are not sure, talk to your doctor or pharmacist before using Symbicort Turbohaler.

Also tell your doctor or pharmacist if you are going to have a general anaesthetic for an operation or for dental work.

Pregnancy and breast-feeding

• If you are pregnant, or planning to get pregnant, talk to your doctor before using Symbicort Turbohaler - do not use Symbicort Turbohaler unless your doctor tells you to.


• If you get pregnant while using Symbicort Turbohaler, do not stop using Symbicort Turbohaler but talk to your doctor immediately.


• If you are breast-feeding, talk to your doctor before using Symbicort Turbohaler.

Driving and using machines

Symbicort Turbohaler is not likely to affect your ability to drive or to use tools or machines.

Important information about some of the ingredients of Symbicort Turbohaler

Symbicort Turbohaler contains lactose, which is a type of sugar. If you have been told by your doctor that you have an intolerance to some sugars, talk to your doctor before using this medicine. The amount of lactose in this medicine does not normally cause problems in people who are lactose intolerant. The excipient lactose contains small amounts of milk proteins, which may cause an allergic reaction.

How to use Symbicort Turbohaler

• Always use Symbicort Turbohaler exactly as your doctor, nurse or pharmacist has told you. Ask one of them for advice if you are not sure.


• It is important to use Symbicort Turbohaler every day, even if you have no asthma or COPD symptoms at the time.


• If you are using Symbicort Turbohaler for asthma, your doctor will want to regularly check your symptoms.

Important information about your asthma or COPD symptoms

If you feel you are getting breathless or wheezy while using Symbicort Turbohaler, you should continue to use Symbicort Turbohaler but go to see your doctor as soon as possible, as you may need additional treatment.

Contact your doctor immediately if:

• Your breathing is getting worse or you often wake up at night with asthma.


• Your chest starts to feel tight in the morning or your chest tightness lasts longer than usual.

These signs could mean that your asthma or COPD is not being properly controlled and you may need different or additional treatment immediately.

Asthma

Use your Symbicort Turbohaler 400/12 every day.

This helps to prevent asthma symptoms from happening.

Adults (18 years and above)

• The usual dose is 1 inhalation, twice a day.


• Your doctor may increase this to 2 inhalations, twice a day.


• If your symptoms are well controlled, your doctor may ask you to take your medicine once a day.

Adolescents (12 to 17 years)

• The usual dose is 1 inhalation, twice a day.


• If your symptoms are well controlled, your doctor may ask you to take your medicine once a day.

A lower strength of Symbicort Turbohaler is available for children aged from 6 to 11 years.

Your doctor (or asthma nurse) will help you to manage your asthma. They will adjust the dose of this medicine to the lowest dose that controls your asthma. However, do not adjust the dose without talking to your doctor (or asthma nurse) first.

Use your separate ‘reliever inhaler’ to treat asthma symptoms when they happen. Always keep your ‘reliever inhaler’ with you to use when you need it.

Do not use Symbicort Turbohaler 400/12 to treat asthma symptoms - use your separate ‘reliever inhaler’.

Chronic Obstructive Pulmonary Disease (COPD)

• Only to be used by adults (aged 18 years and above).


• The usual dose is 1 inhalation twice a day.

Preparing your new Symbicort Turbohaler

Before using your new Symbicort Turbohaler for the first time, you need to prepare it for use as follows:

• Unscrew the cover and lift it off. You may hear a rattling sound.


• Hold your Turbohaler upright with the red grip at the bottom.

• Turn the red grip as far as it will go in one direction. Then turn it as far as it will go in the other direction (it does not matter which way you turn it first). You should hear a click sound.


• Do this again, turning the red grip in both directions.


• Your Turbohaler is now ready for use.

How to take an inhalation

Every time you need to take an inhalation, follow the instructions below.

• 1. Unscrew the cover and lift it off. You may hear a rattling sound.


• 
  2. Hold your Turbohaler upright with the red grip at the bottom.


• 3. Do not hold the mouthpiece when you load your Turbohaler. To load your Turbohaler with a dose, turn the red grip as far as it will go in one direction. Then turn it as far as it will go in the other direction (it does not matter which way you turn it first). You should hear a click sound. Your Turbohaler is now loaded and ready to use. Only load your Turbohaler when you need to use it.


• 4. Hold your Turbohaler away from your mouth. Breathe out gently (as far as is comfortable). Do not breathe out through your Turbohaler.


• 5. Place the mouthpiece gently between your teeth. Close your lips. Breathe in as deeply and as hard as you can through your mouth. Do not chew or bite on the mouthpiece.

• 
  6. Remove your Turbohaler from your mouth. Then breathe out gently. The amount of medicine that is inhaled is very small. This means you may not be able to taste it after inhalation. If you have followed the instructions, you can still be confident that you have inhaled the dose and the medicine is now in your lungs.


• 7. If you are to take a second inhalation, repeat steps 2 to 6.


• 8. Replace the cover tightly after use.

• 9. Rinse your mouth with water after your daily morning and/or evening doses, and spit it out.

Do not try to remove or twist the mouthpiece. It is fixed to your Turbohaler and must not be taken off. Do not use your Turbohaler if it has been damaged or if the mouthpiece has come apart from your Turbohaler.

Cleaning your Turbohaler

Wipe the outside of the mouthpiece once a week with a dry tissue. Do not use water or liquids.

When to start using a new Turbohaler

• The dose indicator tells you how many doses (inhalations) are left in your Turbohaler, starting with 60 doses when it is full.


• The dose indicator is marked in intervals of 10 doses. Therefore it does not show every dose.


• When you first see a red mark at the edge of the indicator window, there are approximately 20 doses left. For the last 10 doses, the background of the dose indicator is red. When the ‘0’ on the red background has reached the middle of the window, you must start using your new Turbohaler.

Note:

• The grip will still twist and ‘click’ even when your Turbohaler is empty.


• The sound that you hear as you shake your Turbohaler is produced by a drying agent and not the medicine. Therefore the sound does not tell you how much medicine is left in your Turbohaler.


• If you load your Turbohaler more than once by mistake before taking your dose, you will still only receive one dose. However, the dose indicator will register all the loaded doses.

If you use more Symbicort Turbohaler than you should

If you use more Symbicort Turbohaler than you should, contact your doctor or pharmacist for advice.

The most common symptoms that may occur if you use more Symbicort Turbohaler than you should are trembling, headache or a rapid heart beat.

If you forget to use Symbicort Turbohaler

• If you forget to take a dose, take it as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose.


• Do not take a double dose to make up for a forgotten dose.

Possible side effects

Like all medicines, Symbicort Turbohaler can cause side effects, although not everybody gets them.

If either of the following happen to you, stop using Symbicort Turbohaler and talk to your doctor immediately:

• Swelling of your face, particularly around your mouth (tongue and/or throat and/or difficulty swallowing) or hives together with difficulty breathing (angioedema) and/or sudden feeling of faintness. This may mean that you are
  having an allergic reaction. This happens rarely, affecting less than 1 in 1,000 people.


• Sudden wheezing after inhaling your medicine.
  
  This happens very rarely, affecting less than 1 in 10,000 people.

Other possible side effects:

Common (affects less than 1 in 10 people)

• Palpitations (awareness of your heart beating), trembling or shaking. If these effects occur, they are usually mild and usually disappear as you continue to use Symbicort Turbohaler.


• Thrush (a fungal infection) in the mouth. This is less likely if you rinse your mouth out with water after using your Turbohaler.


• Mild sore throat, coughing and a hoarse voice.


• Headache.

Uncommon (affects less than 1 in 100 people)

• Feeling restless, nervous or agitated.


• Disturbed sleep.


• Feeling dizzy.


• Nausea (feeling sick).


• Fast heart beat.


• Bruising of the skin.


• Muscle cramps.

Rare (affects less than 1 in 1,000 people)

• Rash, itching.


• Bronchospasm (tightening of the muscles in the airways which causes wheezing). If the wheezing comes on suddenly after using Symbicort Turbohaler stop using Symbicort Turbohaler and talk to your doctor immediately.


• Low levels of potassium in your blood.


• Uneven heart beat.

Very rare (affects less than 1 in 10,000 people)

• Depression.


• Changes in behaviour, especially in children.


• Chest pain or tightness in the chest (angina pectoris).


• An increase in the amount of sugar (glucose) in your blood.


• Taste changes, such as an unpleasant taste in the mouth.


• Changes in your blood pressure.

Inhaled corticosteroids can affect the normal production of steroid hormones in your body, particularly if you use high doses for a long time. The effects include:

• changes in bone mineral density (thinning of the bones)


• cataract (clouding of the lens in the eye)


• glaucoma (increased pressure in the eye)


• a slowing of the rate of growth of children and adolescents


• an effect on the adrenal gland
  
  (a small gland next to the kidney).

These effects are much less likely to happen with inhaled corticosteroids than with corticosteroid tablets.

If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

How to store Symbicort Turbohaler

• Keep out of the reach and sight of children.


• Do not store above 30°C.


• When not in use, Symbicort Turbohaler should be stored with the cover tightened, in order to protect from moisture.


• Do not use Symbicort Turbohaler after the expiry date printed on the carton or on the label of your Turbohaler. The expiry date refers to the last day of that month.


• Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. This will help to protect the environment.

Further information

What Symbicort Turbohaler 400/12 contains

The active substances are budesonide and formoterol.

Each inhaled dose contains 400 micrograms of budesonide and 12 micrograms of formoterol fumarate dihydrate.

The other ingredient is lactose monohydrate (which contains milk proteins).

What Symbicort Turbohaler 400/12 looks like and contents of the pack

Symbicort Turbohaler 400/12 is an inhaler containing your medicine. The inhalation powder is white in colour. Each Turbohaler contains 60 doses and has a white body with a red turning grip.

Symbicort Turbohaler 400/12 is available in packs of 1, 2, 3, 10 or 18 Turbohalers.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

The Marketing Authorisation for Symbicort Turbohaler 400/12 is held by

AstraZeneca UK Ltd

600 Capability Green

Luton

LU1 3LU

UK

Symbicort Turbohaler 400/12 is manufactured by

AstraZeneca AB

S-151 85 Södertälje

Sweden

Symbicort Turbohaler is authorised in the Member States of the EEA under the following names:

Symbicort Turbohaler and Symbicort Turbuhaler. In some countries, the dosage strength refers to the metered dose (400/12), in others the delivered dose (320/9).

To listen to or request a copy of this leaflet in Braille, large print or audio please call, free of charge:

0800 198 5000 (UK only)

Please be ready to give the following information:

Product name

Symbicort Turbohaler 400/12

Reference number

17901/0200

This is a service provided by the Royal National Institute of Blind People.

This leaflet was last approved in February 2010

© AstraZeneca 2010

Symbicort and Turbohaler are trade marks of the AstraZeneca group of companies.

RSP 10 0007

6804040.28

naltrexone Intramuscular

nal-TREX-one

Intramuscular route(Powder for Suspension, Extended Release)

Naltrexone can cause hepatocellular injury when given in excessive doses, is contraindicated in acute hepatitis or liver failure, and its use in patients with active liver disease must be carefully considered in light of its hepatotoxic effects. Patients should be warned of the risk of hepatic injury and advised to stop the use of naltrexone and seek medical attention if they experience symptoms of acute hepatitis .

Commonly used brand name(s)

In the U.S.

• Vivitrol

Available Dosage Forms:

• Powder for Suspension, Extended Release

Therapeutic Class: Ethanol Dependency

Pharmacologic Class: Opioid Antagonist

Uses For naltrexone

Naltrexone injection is used to help narcotic dependents who have stopped taking narcotics to stay drug-free. It is also used to help alcoholics stay alcohol-free. The medicine is not a cure for addiction. It is used as part of an overall program that may include counseling, attending support group meetings, and other treatment recommended by your doctor.

Naltrexone is not a narcotic. It works by blocking the effects of narcotics, especially the "high'' feeling that makes you want to use them. It also may block the "high'' feeling that may make you want to use alcohol. It will not produce any narcotic-like effects or cause mental or physical dependence. It will not prevent you from becoming impaired while drinking alcohol.

Naltrexone will cause withdrawal symptoms in people who are physically dependent on narcotics. Therefore, naltrexone treatment is started after you are no longer dependent on narcotics. The length of time this takes may depend on which narcotic you took, the amount you took, and how long you took it. Before you start using naltrexone, be sure to tell your doctor if you think you are still having withdrawal symptoms.

naltrexone is available only with your doctor's prescription.

Before Using naltrexone

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For naltrexone, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to naltrexone or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of naltrexone injection in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of naltrexone injection in the elderly.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are receiving naltrexone, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using naltrexone with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Alfentanil


• Alphaprodine


• Codeine


• Dihydrocodeine


• Ethylmorphine


• Fentanyl


• Hydrocodone


• Hydromorphone


• Levorphanol


• Meperidine


• Methadone


• Morphine


• Morphine Sulfate Liposome


• Oxycodone


• Oxymorphone


• Propoxyphene


• Sufentanil

Using naltrexone with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Yohimbine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

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

• Bleeding problems (e.g., hemophilia) or


• Kidney disease, moderate to severe or


• Liver disease, mild to moderate or


• Lung or breathing problems or


• Thrombocytopenia (low platelets in the blood)—Use with caution. May make these conditions worse.

• Drug dependence, especially narcotic abuse or dependence, history of or


• Failed the naloxone challenge test (medical test to check your dependence to opioid medicine) or


• Hepatitis, acute or


• Liver disease, severe or


• Opioid withdrawal, acute or


• Positive urine test for opioids or


• Receiving opioid analgesics (e.g., morphine)—Should not be used in patients with these conditions.

Proper Use of naltrexone

A nurse or other trained health professional will give you naltrexone. naltrexone is given as a shot into the buttocks (gluteal) muscle. It is usually given every 4 weeks or once a month.

Naltrexone injection should only be given to alcohol-dependent patients who can abstain from drinking alcohol and does not need an overnight stay in the hospital.

If you miss your scheduled dose, call your doctor to make another appointment as soon as possible.

naltrexone usually comes with a Medication Guide. Read the information carefully and make sure you understand it before receiving naltrexone. If you have any questions, ask your doctor.

Precautions While Using naltrexone

It is very important that your doctor check your progress at regular visits. Your doctor may want to do certain blood and urine tests to see if the medicine is causing unwanted effects.

naltrexone may cause serious problems with your liver. Call your doctor right away if you start having dark urine, pain in the upper stomach, or yellowing of the eyes or skin while you are using naltrexone.

naltrexone may increase your risk of having a lung disease called eosinophilic pneumonia. Tell your doctor right away if you have shortness of breath, coughing, or wheezing after receiving naltrexone.

naltrexone may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash; itching; hoarseness; trouble breathing; trouble swallowing; or any swelling of your hands, face, or mouth while you are using naltrexone.

You will need to stop using opioids (narcotics) for at least 7 to 10 days before you can start receiving naltrexone injection. Your doctor may need to do the naloxone challenge test or a urine test for opioids to make sure you are opioid-free.

naltrexone blocks the "high" feeling you get from narcotic (opioid) drugs, including heroin. Since naltrexone injection may make you more sensitive to lower doses of opioids than you have previously used, you should not use heroin or any other narcotic drugs to overcome what the medicine is doing. You could overdose and develop serious problems.

naltrexone may increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed. Also tell your doctor right away if you have thoughts about hurting yourself. Report any unusual thoughts or behaviors that trouble you, especially if they are new or get worse quickly. Make sure your caregiver knows if you feel tired all the time, sleep a lot more or a lot less than usual, feel hopeless or helpless, or if you have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Also tell your doctor if you have sudden or strong feelings, such as feeling nervous, angry, restless, violent, or scared. Let your doctor know if you or anyone in your family has bipolar disorder (manic-depressive disorder) or has tried to commit suicide.

Remember that use of naltrexone is only part of your treatment. Be sure that you follow all of your doctor's orders, including seeing your therapist and/or attending support group meetings on a regular basis.

Do not try to overcome the effects of naltrexone injection by taking narcotics. To do so may cause coma or death. You may be more sensitive to the effects of narcotics than you were before beginning naltrexone treatment.

Naltrexone injection also blocks the useful effects of narcotics. Always use a non-narcotic medicine to treat pain, diarrhea, or a cough. If you have any questions about the proper medicine to use, check with your doctor.

Naltrexone injection will not prevent you from becoming impaired when you drink alcohol. Do not take naltrexone in order to drive or perform other activities while under the influence of alcohol.

After naltrexone is injected into your body, it is impossible to remove it.

It is recommended that you carry an identification card stating that you are receiving naltrexone injection. You may also need to carry a letter to let others know you are receiving naltrexone in case you have a medical emergency.

You may experience a serious reaction at the site of the naltrexone injection that includes pain, swelling, tenderness, bruising, itching, and redness. Contact your doctor right away if this skin reaction does not improve or becomes worse within two weeks after receiving the injection. Your doctor should also refer you immediately to a surgeon.

You may experience nausea after the first injection of naltrexone that should be mild and subside a few days afterwards. You will be less likely to have nausea with your next injections.

naltrexone may cause some people to become dizzy, drowsy, or less alert than they are normally. If any of these side effects occur, do not drive, use machines, or do anything else that could be dangerous if you are dizzy or are not alert while you are receiving naltrexone injection.

Before you have any medical tests, tell the medical doctor in charge that you are receiving naltrexone. The results of some tests may be affected by naltrexone.

naltrexone Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor or nurse immediately if any of the following side effects occur:

More common

• Bleeding, blistering, burning, coldness, discoloration of the skin, feeling of pressure, hives, infection, inflammation, itching, lumps, numbness, pain, rash, redness, scarring, soreness, stinging, swelling, tenderness, tingling, ulceration, or warmth at the injection site


• body aches or pain


• chills


• congestion


• cough


• difficulty with breathing


• discouragement


• dryness or soreness of the throat


• ear congestion


• fear


• feeling sad or empty


• fever


• headache


• hoarseness


• irritability


• lack of appetite


• loss of interest or pleasure


• loss of voice


• nasal congestion


• nervousness


• rash


• runny nose


• sneezing


• sore throat


• tender, swollen glands in the neck


• trouble concentrating


• trouble sleeping


• trouble with swallowing


• unusual tiredness or weakness


• voice changes

Incidence not known

• Abdominal or stomach cramps or pain


• arm, back, or jaw pain


• black, tarry stools


• bladder pain


• bloating


• bloody or cloudy urine


• bloody stools


• blurred vision


• chest pain or discomfort


• chest tightness or heaviness


• chills


• confusion


• confusion as to time, place, or person


• constipation


• cough


• cough producing mucus


• decreased urination


• diarrhea


• difficult, burning, or painful urination


• dilated neck veins


• dizziness or lightheadedness


• dry mouth


• extreme fatigue


• fainting


• false or unusual sense of well-being


• fast, irregular, pounding, or racing heartbeat or pulse


• frequent urge to urinate


• general feeling of discomfort or illness


• hallucinations or seeing, hearing, or feeling things that are not there


• headache, severe and throbbing


• holding false beliefs that cannot be changed by fact


• hyperventilation


• increase in heart rate


• increase in white blood cells


• indigestion


• irregular breathing


• irritability


• itching, pain, redness, swelling, tenderness, or warmth on the skin


• joint or muscle pain


• lightheadedness


• lower back or side pain


• nausea


• nervousness


• numbness or tingling of the face, hands, or feet


• pain or discomfort in the arms, jaw, back, or neck


• pain, redness, or swelling in the arm or leg


• pounding in the ears


• rapid breathing


• redness and soreness of the eyes


• restlessness


• seizures


• severe nausea or vomiting


• shaking


• shivering


• shortness of breath


• skin rash


• slow or fast heartbeat


• sores in the mouth


• stomach cramps


• stomach pain


• sudden shortness of breath or troubled breathing


• sunken eyes


• sweating


• swelling of the face, fingers, feet, or lower legs


• swollen, painful, or tender lymph glands in the neck, armpit, or groin


• tenderness


• thirst


• tightness in the chest


• tooth or gum pain


• trouble sleeping


• troubled breathing


• unusual excitement, nervousness, or restlessness


• vomiting


• vomiting of blood or material that looks like coffee grounds


• watery or bloody diarrhea


• weight gain


• wheezing


• wrinkled skin

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

Symptoms of overdose

• Sleepiness or unusual drowsiness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Difficulty with moving


• muscle stiffness


• swelling or redness in the joints

Incidence not known

• Bleeding after defecation


• bloated


• change in taste


• decreased interest in sexual intercourse


• drowsiness


• excess air or gas in the stomach or intestines


• feeling of warmth


• feeling unusually cold


• full feeling


• heartburn


• inability to have or keep an erection


• increased sweating


• loss in sexual ability, desire, drive, or performance


• loss of taste


• night sweats


• passing gas


• redness of the face, neck, arms, and occasionally, upper chest


• relaxed and calm


• sleepiness


• stuffy nose


• sudden sweating


• toothache


• uncomfortable swelling around anus


• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness


• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

See also: naltrexone Intramuscular side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More naltrexone Intramuscular resources

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

Compare naltrexone Intramuscular with other medications

• Alcohol Dependence
• Fibromyalgia
• Opiate Dependence
• Trichotillomania

Toctino 10mg and 30mg soft capsules

1. Name Of The Medicinal Product

Toctino^®

Toctino^®

2. Qualitative And Quantitative Composition

Each soft capsule contains 10mg or 30mg of alitretinoin.

This medicinal product contains the excipients soya-bean oil and sorbitol.

For a full list of excipients, see section 6.1 “List of excipients”.

3. Pharmaceutical Form

Soft capsule

The Toctino 10mg capsule is an opaque brown soft capsule imprinted with “A1” in white.

The Toctino 30mg capsule is an opaque red-brown soft capsule imprinted with “A3” in white.

4. Clinical Particulars

4.1 Therapeutic Indications

Toctino is indicated for use in adults who have severe chronic hand eczema that is unresponsive to treatment with potent topical corticosteroids.

Patients in whom the eczema has predominantly hyperkeratotic features are more likely to respond to treatment than in those in whom the eczema predominantly presents as pompholyx (See section 5.1 “Pharmacodynamic properties”).

4.2 Posology And Method Of Administration

Toctino should only be prescribed by dermatologists, or physicians with experience in the use of systemic retinoids who have full understanding of the risks of systemic retinoid therapy and monitoring requirements. Prescriptions of Toctino for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Toctino should occur on the same day. Dispensing of Toctino should occur within a maximum of 7 days of the prescription.

The recommended dose range for Toctino is 10mg-30mg once daily.

The recommended start dose for Toctino is 30mg once daily. A dose reduction to 10mg once daily may be considered in patients with unacceptable adverse reactions to the higher dose. In studies investigating 10mg and 30mg daily doses, both doses resulted in clearing of the disease. The 30mg dose provided a more rapid response and a higher response rate. The 10mg daily dose was associated with fewer adverse events (see section 4.4 “Special warnings and precautions for use” and section 5.1 “Pharmacodynamic Properties”).

A treatment course of Toctino may be given for 12 to 24 weeks depending on response. Discontinuation of therapy should be considered for patients who still have severe disease after the initial 12 weeks of treatment. In the event of relapse, patients may benefit from further treatment courses of Toctino.

The capsules should be taken with a meal once daily.

Toctino should not be prescribed if the patient's eczema can be adequately controlled by standard measures, including skin protection, avoidance of allergens and irritants, and treatment with potent topical corticosteroids.

Children

Toctino is not recommended for use in patients under 18 years of age.

4.3 Contraindications

Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.6 “Pregnancy and lactation”).

Toctino is contraindicated in woman of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme are met (see section 4.4 “Special warnings and special precautions for use”).

Toctino contains soya oil. Patients who are allergic to peanut, soya or with rare hereditary fructose intolerance should not take this medicine.

Toctino is contraindicated in breastfeeding.

Toctino is also contraindicated in patients

• With hepatic insufficiency

• With severe renal insufficiency

• With uncontrolled hypercholesterolaemia

• With uncontrolled hypertriglyceridaemia

• With uncontrolled hypothyroidism

• With hypervitaminosis A

• With hypersensitivity either to alitretinoin, to other retinoids or to any of the excipients, in particular in case of allergies to peanut or soya

• Receiving concomitant treatment with tetracyclines (see section 4.5 “Interactions with other medicinal products and other forms of interactions”)

4.4 Special Warnings And Precautions For Use

Pregnancy Prevention Programme

This medicinal product is TERATOGENIC.

Toctino is contraindicated in women of childbearing potential unless all of the following conditions of the Pregnancy Prevention Programme are met:

• She understands the teratogenic risk

• She understands the need for rigorous follow-up, on a monthly basis

• She understands and accepts the need for effective contraception, without interruption, 1 month before starting treatment, throughout the duration of treatment and 1 month after the end of treatment. At least one and preferably two complementary forms of contraception including a barrier method should be used

• Even if she has amenorrhoea she must follow all of the advice on effective contraception

• She should be capable of complying with effective contraceptive measures

• She is informed and understands the potential consequences of pregnancy and the need to rapidly consult if there is a risk of pregnancy

• She understands the need and accepts to undergo pregnancy testing before, during and 5 weeks after the end of treatment

• She has acknowledged that she has understood the hazards and necessary precautions associated with the use of Toctino

These conditions also concern women who are not currently sexually active unless the prescriber considers that there are compelling reasons to indicate that there is no risk of pregnancy.

The prescriber must ensure that:

• The patient complies with the conditions for pregnancy prevention as listed above, including confirmation that she has an adequate level of understanding

• The patient has acknowledged the aforementioned conditions

• The patient has used at least one and preferably two methods of effective contraception including a barrier method for at least 1 month prior to starting treatment and is continuing to use effective contraception throughout the treatment period and for at least 1 month after cessation of treatment

• Negative pregnancy test results have been obtained before, during and 5 weeks after the end of treatment. The dates and results of pregnancy tests should be documented

Contraception

Female patients must be provided with comprehensive information on pregnancy prevention and should be referred for contraceptive advice if they are not using effective contraception.

As a minimum requirement, female patients at potential risk of pregnancy must use at least one effective method of contraception. Preferably the patient should use two complementary forms of contraception including a barrier method. Contraception should be continued for at least 1 month after stopping treatment with Toctino, even in patients with amenorrhea.

Pregnancy testing

According to local practice, medically supervised pregnancy tests with a minimum sensitivity of 25mIU/mL are recommended to be performed in the first 3 days of the menstrual cycle, as follows:

One month prior to starting therapy

In order to exclude the possibility of pregnancy prior to starting contraception, it is recommended that an initial medically supervised pregnancy test should be performed and its date and result recorded. In patients without regular menses, the timing of this pregnancy test should reflect the sexual activity of the patient and should be undertaken approximately 3 weeks after the patient last had unprotected sexual intercourse. The prescriber should educate the patient about contraception.

At the start of therapy

A medically supervised pregnancy test should also be performed during the consultation when Toctino is prescribed or in the 3 days prior to the visit to the prescriber, and should have been delayed until the patient had been using effective contraception for at least 1 month. This test should ensure the patient is not pregnant when she starts treatment with Toctino.

Follow-up visits

Follow-up visits should be arranged at 28 day intervals. The need for repeated medically supervised pregnancy tests every month should be determined in consideration amongst other of the patient's sexual activity and recent menstrual history (abnormal menses, missed periods or amenorrhea). Where indicated, follow-up pregnancy tests should be performed on the day of the prescribing visit or in the 3 days prior to the visit to the prescriber.

End of treatment

Five weeks after stopping treatment, women should undergo a final pregnancy test to exclude pregnancy.

Prescribing and dispensing restrictions

Prescriptions of Toctino for women of childbearing potential should be limited to 30 days of treatment and continuation of treatment requires a new prescription. Ideally, pregnancy testing, issuing a prescription and dispensing of Toctino should occur on the same day. Dispensing of Toctino should be completed within a maximum of 7 days of the prescription.

Male patients

Small amounts of alitretinoin have been detected in the semen of healthy volunteers receiving 40 mg of alitretinoin and there is no indication of drug accumulation in semen. Assuming complete vaginal absorption of these amounts would have a negligible effect on the endogenous plasma levels of the female partner and therefore does not appear to pose a risk to the foetus if the partner is pregnant. Based on non-clinical findings, male fertility may be compromised by treatment with Toctino (see section 5.3 “Preclinical safety data”).

Male patients should be reminded that they must not share their medication with anyone, particularly not females.

Additional precautions

Patients should be instructed never to give this medicinal product to another person and to return any unused capsules to their pharmacist at the end of treatment.

Patients should not donate blood during therapy and for 1 month following discontinuation of Toctino because of the potential risk to the foetus of a pregnant transfusion recipient.

Educational material

In order to assist prescribers, pharmacists and patients in avoiding foetal exposure to alitretinoin, the Marketing Authorisation Holder will provide educational material to reinforce the warnings about the teratogenicity of Toctino, to provide advice on contraception before therapy is started and to provide guidance on the need for pregnancy testing. Full patient information about the teratogenic risk and the strict pregnancy prevention measures as specified in the Pregnancy Prevention Programme should be given by the physician to all patients, both male and female.

Psychiatric disorders

Depression, aggravated depression, anxiety, aggressive tendencies, mood alterations, psychotic symptoms, and very rarely, suicidal ideation, suicide attempts and suicide have been reported in patients treated with systemic retinoids. Particular care needs to be taken in patients with a history of depression and patients on alitretinoin treatment should therefore be observed for signs of depression and referred for appropriate treatment if necessary. However, discontinuation of alitretinoin may be insufficient to alleviate symptoms and therefore further psychiatric or psychological evaluation may be necessary.

UV light

The effects of UV light are enhanced by retinoid therapy, therefore patients should avoid excessive exposure to sunlight and the unsupervised use of sun lamps. Where necessary a sun-protection product with a high protection factor of at least SPF 15 should be used.

Patients who experience dryness of the skin and lips should be advised to use a skin moisturising ointment or cream and a lip balm.

Musculo-skeletal and connective tissue disorders

Treatment with other systemic retinoids has been associated with bone changes including premature epiphyseal closure, hyperostosis, and calcification of tendons and ligaments.

Myalgia, arthralgia and increased serum creatinine phosphokinase values have been observed in patients treated with alitretinoin.

Eye disorders

Treatment with alitretinoin has been associated with dry eyes. The symptoms usually resolve after discontinuation of therapy. Dry eyes can be helped by the application of a lubricating eye ointment or by the application of tear replacement therapy. Intolerance to contact lenses may occur which may necessitate the patient wearing glasses during treatment.

Treatment with systemic retinoids has been associated with corneal opacities and keratitis. Decreased night vision has been observed in patients treated with alitretinoin. These effects usually resolve after discontinuation of therapy.

Patients experiencing visual difficulties should be referred to an ophthalmologist. Withdrawal of alitretinoin may be necessary.

Benign intracranial hypertension

Treatment with systemic retinoids, including alitretinoin, has been associated with the occurrence of benign intracranial hypertension, some of which involved concomitant use of tetracyclines (see section 4.3 “Contraindications” and section 4.5 “Interaction with other medicinal products and other forms of interaction”). Signs and symptoms of benign intracranial hypertension include headache, nausea and vomiting, visual disturbances and papilloedema. Patients who develop signs of benign intracranial hypertension should discontinue alitretinoin immediately.

Lipid Metabolism

Alitretinoin has been associated with an increase in plasma cholesterol and triglyceride levels. Serum cholesterol and triglycerides (fasting values) should be monitored.

Alitretinoin should be discontinued if hypertriglyceridaemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur (see section 4.8 “Undesirable effects”). Triglyceride levels in excess of 800mg/dL (9mmol/L) are sometimes associated with acute pancreatitis, which may be fatal.

Thyroid function

Changes in thyroid function tests have been observed in patients receiving alitretinoin, most often noted as a reversible reduction in thyroid stimulating hormone (TSH) levels and T4 (free thyroxine).

Hepatobiliary disorders

Treatment with other systemic retinoids has been associated with transient and reversible increases in liver transaminases. In the event of persistent clinically relevant elevation of transaminase levels, reduction of the dose or discontinuation of treatment should be considered.

Gastrointestinal disorders

Systemic retinoids have been associated with IBD (inflammatory bowel disease, including regional ileitis) in patients without a history of intestinal disorders. If severe diarrhoea is observed, diagnosis of IBD should be considered and alitretinoin should be discontinued immediately.

Allergic reactions

Anaphylactic reactions have been rarely reported in systemic retinoids, in some cases after previous topical exposure to retinoids. Allergic cutaneous reactions are reported infrequently. Serious cases of allergic vasculitis, often with purpura (bruises and red patches) of the extremities and extracutaneous involvement have been reported. Severe allergic reactions necessitate interruption of therapy and careful monitoring.

High risk patients

In patients with diabetes, obesity, cardiovascular risk factors or a lipid metabolism disorder undergoing treatment with alitretinoin, more frequent checks of serum values for lipids may be necessary. It is recommended that these patients are started with 10mg once daily and titrated up to the maximum dose of 30mg if necessary.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Pharmacokinetic interaction

Alitretinoin is metabolised by cytochrome P450 3A4 (CYP3A4).

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.

Co-administration with CYP3A4 inhibitors such as ketoconazole increases the plasma level of alitretinoin and dose reduction may be required. The effects of other inhibitors of CYP3A4 have not been studied. Alitretinoin did not affect the pharmacokinetics of ketoconazole.

A 16% reduction of simvastatin plasma levels was observed when co-administered with alitretinoin.

The effects on other similar medicinal products have not been studied. Simvastatin did not affect the pharmacokinetics of alitretinoin.

No pharmacokinetic interactions were observed when alitretinoin was co-administered with ciclosporin or the oral contraceptive ethinyl estradiol and norgestimate.

Pharmacodynamic interactions

Patients should not take vitamin A or other retinoids as concurrent medication due to the risk of hypervitaminosis A.

Cases of benign intracranial hypertension (pseudotumour cerebri) have been reported with concomitant use of retinoids and tetracyclines. Therefore, concomitant treatment with tetracyclines must be avoided (see sections 4.3 “Contraindications” and section 4.4 “Special warnings and precautions for use”).

4.6 Pregnancy And Lactation

Pregnancy is an absolute contraindication to treatment with Toctino (see section 4.3, “Contraindications”). If pregnancy does occur in spite of the pregnancy prevention precautions during treatment with Toctino or in the month following discontinuation of therapy, there is a great risk of very severe and serious malformation of the foetus.

Alitretinoin is a retinoid and therefore is a potent teratogen. The foetal malformations associated with exposure to retinoids include central nervous system abnormalities (hydrocephalus, cerebellar malformation/ abnormalities, microcephaly), facial dysmorphia, cleft palate, external ear abnormalities (absence of external ear, small or absent external auditory canals), eye abnormalities (microphthalmia), cardiovascular abnormalities (conotruncal malformations such as tetralogy of Fallot, transposition of great vessels, septal defects), thymus gland abnormality and parathyroid gland abnormalities. There is also an increased incidence of spontaneous abortion.

If pregnancy occurs in a woman treated with Toctino, treatment must be stopped and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.

Lactation

Alitretinoin is highly lipophilic, therefore the passage of alitretinoin into human milk is very likely. Due to the potential risk for the exposed child, the use of alitretinoin is contraindicated during breastfeeding.

Fertility

Small amounts of alitretinoin have been detected in the semen of healthy volunteers receiving 40mg of alitretinoin and there is no indication of drug accumulation in semen. In the event of complete vaginal absorption of these amounts, this would have a negligible effect on the endogenous plasma levels of the female partner and therefore does not appear to pose a risk to the foetus if the partner is pregnant. Based on non-clinical findings, male fertility may be compromised by treatment with Toctino (see section 5.3 “Preclinical safety data”).

4.7 Effects On Ability To Drive And Use Machines

Decreased night vision has been reported in patients treated with alitretinoin and other retinoids. Patients should be advised of this potential problem and warned to be cautious when driving or operating machines.

4.8 Undesirable Effects

The most frequent adverse drug reactions (ADRs) observed under alitretinoin therapy are headache (30mg: 21%; 10mg: 11%), flushing (30mg: 5.9%; 10mg: 1.6% ), and laboratory changes consisting of increased levels of triglycerides (30mg: 35.4%; 10mg: 17.0% ), increased cholesterol (30mg: 27.8%; 10mg: 16.7%), decreased levels of thyroid stimulating hormone (TSH, 30mg: 8.4%; 10mg: 6.0%) and decreased levels of free T4 (30mg: 10.5%; 10mg: 2.9%). These reversible ADRs are dose dependent and may therefore be alleviated by dose reduction.

	Very common (	Common (	Uncommon (	Rare (
Blood and lymphatic system disorders		Anaemia, increased iron binding capacity, monocytes decreased; thrombocytes increased
Endocrine Disorders		TSH decreased, free T4 decreased
Nervous system disorders	Headache			Benign intracranial hypertension
Eye disorders		Conjunctivitis, dry eye, eye irritation	Blurred vision, cataract
Vascular disorders		Flushing		Vasculitis
Respiratory, thoracic and mediastinal disorders			Epistaxis
Hepatobiliary disorders		Transaminase increased1)
Skin and subcutaneous tissues disorders		Dry skin, dry lips, cheilitis, eczema1) , dermatitis1) , erythema, alopecia	Pruritus, rash, skin exfoliation, asteatotic eczema
Musculo-skeletal and connective tissue disorders		Arthralgia1) , myalgia1	Exostosis, (hyperostosis), ankylosing spondylitis
Investigations	Hypertriglyceridemia, high density lipoprotein decreased, hypercholesterolemia	Blood creatinine phosphokinase increased

¹⁾ The incidence of adverse events was not higher than those observed in the corresponding placebo group.

Psychiatric effects, in particular depression, and mood changes and suicidal ideation, have been associated with retinoids. In clinical studies, where patients with a history or active psychiatric disorders were excluded patients have been monitored for depression using the CES-D (Center for Epidemiological Studies - Depression) score. Treatment with alitretinoin was not associated with changes in the CES-D score.

The following adverse events have not been observed in clinical trials with alitretinoin, but have been observed with other retinoids: inflammatory bowel disease, diabetes mellitus, colour blindness (colour vision deficiencies), and contact lens intolerance (see section 4.4 “Special warnings and precautions for use”).

Changes in bone mineralisation and extra-osseous calcifications have been associated with systemic retinoid treatment. In clinical studies with alitretinoin, degenerative changes of the spine and ligamentous calcifications were frequent findings in patients with chronic hand eczema before treatment (baseline), with minor progression in a small number of patients during treatment. These observations were consistent with age dependent degenerative changes. Assessments of bone density (DXA) did not indicate a dose dependent effect on bone mineralisation.

4.9 Overdose

Alitretinoin is a derivative of vitamin A. Alitretinoin has been administered in oncological clinical studies at dosages of more than 10 times the therapeutic dosage given for chronic hand eczema. The adverse effects observed were consistent with retinoid toxicity, and included severe headache, diarrhoea, facial flushing, hypertriglyceridaemia. These effects were reversible.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC code: D11AX19

Mechanism of action

The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinisation, sebum secretion and immunomodulation. Unlike other retinoids, which are specific agonists of either RAR or RXR receptors, alitretinoin binds to members of both receptor families. The mechanism of action of alitretinoin in chronic hand eczema is unknown. Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation. CXCR3 ligands and CCL20 chemokines, expressed in eczematous skin lesions, are down-regulated by alitretinoin in cytokine-stimulated keratinocytes and dermal endothelial cells. In addition, alitretinoin suppresses the expansion of cytokine-activated leucocyte subsets and antigen presenting cells.

It has been observed that in humans alitretinoin only minimally affects sebum secretion.

Clinical efficacy

The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) refractory to topical corticosteroids has been established in two randomised, double blind, placebo-controlled Phase 3 studies.

The primary endpoint in these studies was the proportion of patients achieving Physicians Global Assessment (PGA) ratings of clear or almost clear hands at the end of therapy. The treatment duration was 12 to 24 weeks.

The BACH (Benefit of Alitretinoin in Chronic Hand Dermatitis Study) included 1032 severe CHE patients who had no response or a transient response (initial improvement and worsening of disease despite continued treatment) to potent topical corticosteroids or who were intolerant of potent topical corticosteroids. All phenotypes of CHE were included: hyperkeratosis (87%), pompholyx (27%), fingertip dermatitis (43%), and other (15%). Essentially all patients had signs of skin inflammation, comprising of erythema and/or vesicles. Treatment with alitretinoin led to a significantly higher proportion of patients with clear/almost clear hands, compared to placebo. The response was dose dependent (see Table 2). Response rates for different CHE subtypes were also dose dependent, except for patients with pompholyx (see Table 3).

Table 2: Primary Efficacy Parameter - Results

	Alitretinoin
Primary Endpoint	10 mg	30 mg	Placebo
ITT Population	N=418	N=409	N=205
PGA at end of study Total Response Rate Clear Almost clear	115 (27.5%) 39 ( 9.3%) 76 (18.2%)	195 (47.7%) 90 (22.0%) 105 (25.7%)	34 (16.6%) 6 ( 2.9%) 28 (13.7%)
Comparison to placebo	P=0.004	P=<0.001	N/A

Table 3: Response rate by CHE subtype

CHE subtype (% of ITT population)	Hyperkeratotic (64%)	Hyperkeratotic/ Pompholyx (22%)	Pompholyx (5%)
Response rate (PGA)	30mg: 54% 10 mg: 30% Placebo: 12%	30mg: 33% 10 mg: 23% Placebo: 12%	30mg: 33% 10 mg: 22% Placebo: 30%

Secondary endpoints included the proportion of patients achieving at least mild disease, time to achieving clear to almost clear hands, reduction in total lesion symptom score, patient global assessment (PaGA) of disease severity, reduction in extent of disease (see Table 4). Patients with clear/almost clear hands at end of treatment were followed up for 24 weeks. During that period no active drug treatment for CHE was allowed. Relapse was defined as 75% of the initial total lesion symptom score.

Table 4: Secondary Efficacy Parameters - Results

	Alitretinoin
Efficacy Variable	10 mg	30 mg	Placebo
ITT Population	N=418	N=409	N=205
Partial Response Rate (clear, almost clear or mild disease)	207 (49.5%)	254 (62.1%)	74 (36.1%)
PaGA (clear or almost clear)	101 (24.2%)	163 (39.9%)	31 (15.1%)
mTLSS (mean % change from baseline)	-50.79 (n=411)	-60.80 (n=408)	-37.30 (n=204)
Extent of disease (mean % change from baseline)	-40.01 (n=402)	-54.15 (n=391)	-31.93 (n=197)

The numbers of responding patients without observed relapse at the end of the 24-weeks follow-up period is given in Table 5 below. In this analysis, the majority of responders given 10mg and 30mg alitretinoin did not relapse by the end of the follow-up period.

Table 5: Relapse Rates* at the End of Follow-up

	Alitretinoin	Placebo N=205
	10 mg N=418	30 mg N=409
Responders	115 (100%)	195 (100%)	34 (100%)
No Relapse	81 (70.4%)	122 (62.6%)	19 (55.9%)

* Corresponds to a last-observation-carried-forward (LOCF) computation

A follow-up study (the second Phase 3 study) investigated the efficacy and safety of a second course of treatment both in patients who previously responded (Cohort A) and in patients who did not (Cohort B). Cohort A patients who responded in the previous study but who relapsed were randomised to the same dose they received in their initial treatment (10 or 30mg) or to placebo in a 2:1 ratio. 80% of relapsing patients who again received the 30 mg dose achieved clear/almost clear hands vs. 8% of the corresponding placebo group (p<0.001). 48% of relapsing patients who again received the 10 mg dose achieved clear/almost clear hands vs. 10% of the corresponding placebo group (p=0.1). Patients who responded to treatment with placebo in the previous study also received placebo in this follow-up study. Many of these patients responded again to treatment with placebo (69.2%).

5.2 Pharmacokinetic Properties

Absorption

The absorption of alitretinoin from the gastro-intestinal tract is variable and dose-proportional over the therapeutic range from 10-30mg. The absolute bioavailability of alitretinoin has not been determined. When alitretinoin is taken with food, the systemic exposure is enhanced by a factor of 4 and the variability of exposure is decreased. Therefore, alitretinoin should be taken with a meal.

Distribution

Alitretinoin strongly binds to plasma proteins. The volume of distribution of alitretinoin in man has not been determined, but animal studies indicate a volume of distribution greater than the extracellular volume.

Metabolism

Alitretinoin is metabolised by oxidation in the liver by CYP3A4 isoenzymes into 4-oxo-alitretinoin. Both compounds undergo isomerisation into all-trans retinoic acid and 4-oxo-all-trans retinoic acid. After oral administration, the contribution of the metabolites in plasma to the systemic exposure of alitretinoin is approximately 35% to 80% for 4-oxo-alitretinoin. The major metabolite 4-oxo-alitretinoin is further glucuronidated and eliminated in urine. Alitretinoin is degraded similarly to vitamin A by sequential cleavage of the carbon-side chain.

During a 12-to 24-week treatment period with 10 or 30mg, the exposure to alitretinoin remained stable.

Elimination

Alitretinoin is an endogenous retinoid. Alitretinoin concentrations return to normal range within 1 to 3 days after treatment cessation.

Excretion of radio-labelled alitretinoin was complete with approximately 94% of the dose recovered. Radio-labelled material was eliminated mainly in urine and a smaller fraction (approx. 30%) in faeces. The most abundant excretion compound is the glucuronide of 4-oxo-alitretinoin amounting to 6.5% of the dose in urine.

Elimination half-life of unchanged alitretinoin ranges between 2 to 10 hours. Alitretinoin and its 4-oxo-metabolite do not accumulate.

Pharmacokinetic in special populations

In a pharmacokinetic study in patients, gender, weight and age did not affect the pharmacokinetics of alitretinoin.

The pharmacokinetics of alitretinoin in CHE patients was similar to that in healthy volunteers.

Alitretinoin kinetics have not been studied in patients with hepatic or with severe renal insufficiency or in patients below 18 years (see section 4.3).

5.3 Preclinical Safety Data

Acute toxicity

As with other retinoids, the acute toxicity of alitretinoin was low in mice and rats. The LD₅₀ after intraperitoneal administration was >4000 mg/kg after 24 hours and 1400 mg/kg after 10 days. The approximate LD₅₀ after oral administration in rats was 3000 mg/kg.

Chronic toxicity

Alitretinoin was tested in long-term studies up to 9 months in dogs and 6 months in rats. Signs of toxicity were dose-related and occurred at exposures similar to the human therapeutic exposure based on AUC. Effects were characteristic for retinoids (consistent with hypervitaminosis A), and were generally spontaneously reversible.

Teratogenicity

Like other retinoids, alitretinoin has been shown to be teratogenic in vitro and in vivo.

Due to the teratogenic potential of alitretinoin, women of childbearing potential must adhere to strict pregnancy prevention measurers during and 1 month following alitretinoin therapy (see section 4.3 “Contraindications”, section 4.4 “Special warnings and special precautions for use” and section 4.6 “Pregnancy and lactation”).

Fertility

Alitretin