FusePaq Synapryn

Generic Name: tramadol (Oral route)

TRAM-a-dol

Commonly used brand name(s)

In the U.S.

• ConZip


• FusePaq Synapryn


• Rybix ODT


• Ryzolt


• Ultram


• Ultram ER

Available Dosage Forms:

• Capsule, Extended Release


• Tablet, Extended Release


• Tablet, Disintegrating


• Tablet


• Suspension

Therapeutic Class: Analgesic

Chemical Class: Opioid

Uses For FusePaq Synapryn

Tramadol is used to relieve moderate to moderately severe pain, including pain after surgery. The extended-release or long-acting tablets are used for chronic ongoing pain.

Tramadol belongs to the group of medicines called opioid analgesics. It acts in the central nervous system (CNS) to relieve pain. When tramadol is used for a long time, it may become habit-forming (causing mental or physical dependence). Physical dependence may lead to side effects when you stop taking the medicine.

This medicine is available only with your doctor's prescription.

Before Using FusePaq Synapryn

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

Allergies

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

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of Rybix™ ODT, Ryzolt™, and Ultram® tablets in children younger than 16 years of age. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of Ultram® ER extended-release tablets 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 tramadol in the elderly. However, elderly patients are more likely to have unwanted side effects (e.g., constipation; lightheadedness, dizziness, or fainting; stomach upset; weakness) and age-related liver, kidney, or heart problems, which may require caution and an adjustment in the dose for patients receiving tramadol.

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 taking this medicine, 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 this medicine 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.

• Rasagiline


• Selegiline

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acetophenazine


• Amitriptyline


• Amoxapine


• Bromperidol


• Carbamazepine


• Chlorpromazine


• Chlorprothixene


• Citalopram


• Clobazam


• Clomipramine


• Clorgyline


• Clovoxamine


• Clozapine


• Cyclobenzaprine


• Desipramine


• Desvenlafaxine


• Dothiepin


• Doxepin


• Duloxetine


• Escitalopram


• Ethopropazine


• Femoxetine


• Fluoxetine


• Flupenthixol


• Fluphenazine


• Fluvoxamine


• Haloperidol


• Imipramine


• Isocarboxazid


• Ketamine


• Linezolid


• Lofepramine


• Loxapine


• Melperone


• Mesoridazine


• Methotrimeprazine


• Milnacipran


• Mirtazapine


• Moclobemide


• Molindone


• Nortriptyline


• Olanzapine


• Paroxetine


• Penfluridol


• Perphenazine


• Phenelzine


• Pimozide


• Pipotiazine


• Prochlorperazine


• Promazine


• Promethazine


• Propiomazine


• Protriptyline


• Remoxipride


• Risperidone


• Sertraline


• Sulpiride


• Tapentadol


• Thiethylperazine


• Thioridazine


• Thiothixene


• Tranylcypromine


• Trifluoperazine


• Triflupromazine


• Trimeprazine


• Trimipramine


• Venlafaxine


• Vilazodone


• Zuclopenthixol

Using this medicine 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.

• Digoxin


• Quinidine


• Warfarin

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

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

• Alcohol abuse, history of or


• CNS depression or


• Depression, history of or


• Drug abuse, history of or


• Head injury or


• Hormonal problems or


• Increased pressure in the head or


• Infections of the central nervous system (CNS) or


• Mental illness, history of or


• Phenylketone allergy, history of or


• Respiratory depression (hypoventilation or slow breathing) or


• Seizures or epilepsy, history of or


• Stomach problems, severe—Use with caution. The chance of serious side effects may be increased.

• Breathing or lung problems (e.g., asthma, hypercapnia), severe—Should not be used in patients with this condition.

• Kidney disease or


• Liver disease (including cirrhosis)—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Phenylketonuria (PKU)—The orally disintegrating tablet contains phenylalanine, which can make this condition worse.

Proper Use of tramadol

This section provides information on the proper use of a number of products that contain tramadol. It may not be specific to FusePaq Synapryn. Please read with care.

Take this medicine only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

If you think that this medicine is not working as well after you have been taking it for a few weeks, do not increase the dose. Instead, check with your doctor.

If you are using the disintegrating tablet, make sure your hands are dry before you handle the tablet. Do not open the blister pack that contains the tablet until you are ready to take it. Remove the tablet from the blister pack by peeling back the foil, then taking the tablet out. Do not push the tablet through the foil. Do not break, crush, or chew it. Place the tablet in your mouth. It should melt quickly. After the tablet has melted, swallow or take a sip of water.

Swallow the extended-release tablets whole with liquids. Do not break, crush, or chew it.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For chronic pain:
  
  • For oral dosage form (extended-release tablets):
    
    • Adults—At first, 100 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 300 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults and teenagers 16 years of age and older—At first, 50 to 100 milligrams (mg) every four to six hours as needed. Your doctor may increase your dose as needed. However, the dose is usually not more than 400 mg per day.
    
    
    • Children younger than 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  

• For moderate to severe pain:
  
  • For oral dosage form (disintegrating tablets):
    
    • Adults and teenagers 16 years of age and older—At first, 50 to 100 milligrams (mg) every four to six hours as needed. Your doctor may increase your dose as needed. However, the dose is usually not more than 400 mg per day.
    
    
    • Children younger than 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For oral dosage form (tablets):
    
    • Adults and teenagers 16 years of age and older—At first, 25 milligrams (mg) per day, taken every morning. Your doctor may increase your dose as needed. However, the dose is usually not more than 400 mg per day.
    
    
    • Children younger than 16 years of age—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using FusePaq Synapryn

It is very important that your doctor check your progress at regular visits to make sure the medicine is working properly and to check for any unwanted effects.

This medicine will add to the effects of alcohol and other CNS depressants (medicine that makes you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; medicine for seizures or barbiturates; muscle relaxants; or anesthetics, including some dental anesthetics. Do not drink alcoholic beverages, and check with your doctor or dentist before taking any of these medicines while you are using this medicine.

Make sure your doctor knows about all the other medicines you are using. This medicine may increase your risk for seizures. (convulsions) and may cause a serious condition called serotonin syndrome.

This medicine can increase thoughts of suicide. Tell your doctor right away if you start to feel more depressed or 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 have trouble sleeping, get upset easily, have a big increase in energy, or start to act reckless. Tell your doctor if you have any 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.

This medicine may cause serious allergic reactions, including 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; swelling of your hands, face, or mouth; or chest pain while you are using this medicine.

This medicine may cause some people to become drowsy, dizzy, lightheaded, or less alert than they are normally. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert.

Make sure your doctor knows if you are pregnant, may be pregnant, or planning to become pregnant.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. Getting up slowly may help lessen this problem.

Nausea or vomiting may occur, especially after the first couple of doses. This effect may go away if you lie down for awhile. However, if nausea or vomiting continues, check with your doctor. Lying down for a while may also help relieve some other side effects, such as dizziness or lightheadedness that may occur.

Before having any kind of surgery (including dental surgery) or emergency treatment, tell the doctor or dentist in charge that you are taking this medicine. Taking tramadol together with medicines that are used during surgery or dental or emergency treatments may cause increased side effects.

If you think you or someone else may have taken an overdose of tramadol, get emergency help at once. Signs of an overdose include convulsions (seizures); difficult or troubled breathing; irregular, fast or slow, or shallow breathing; pale or blue lips, fingernails, or skin; pinpoint pupils of the eyes, or shortness of breath.

Do not stop suddenly taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent a possible worsening of your condition and reduce the possibility of withdrawal symptoms such as anxiety, diarrhea, headache, nausea, shivering, sweating, tremors, or trouble with sleeping.

FusePaq Synapryn 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 immediately if any of the following side effects occur:

Less common or rare

• Abdominal or stomach fullness


• abnormal or decreased touch sensation


• blisters under the skin


• bloating


• blood in the urine


• blood pressure increased


• blurred vision


• change in walking and balance


• chest pain or discomfort


• chills


• convulsions (seizures)


• darkened urine


• difficult urination


• dizziness or lightheadedness when getting up from a lying or sitting position


• fainting


• fast heartbeat


• frequent urge to urinate


• gaseous abdominal or stomach pain


• heart rate increased


• indigestion


• irregular heartbeat


• loss of memory


• numbness and tingling of the face, fingers, or toes


• numbness, tingling, pain, or weakness in the hands or feet


• pain in the arms, legs, or lower back, especially pain in the calves or heels upon exertion


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


• pains in the stomach, side, or abdomen, possibly radiating to the back


• pale bluish-colored or cold hands or feet


• recurrent fever


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


• severe cramping


• severe nausea


• severe redness, swelling, and itching of the skin


• shortness of breath


• sweats


• trembling and shaking of the hands or feet


• trouble performing routine tasks


• weak or absent pulses in the legs


• yellow eyes or skin

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

Symptoms of overdose

• Change in consciousness


• decreased awareness or responsiveness


• difficulty with breathing


• lack of muscle tone


• lightheadedness


• loss of consciousness


• pinpointed pupils of the eyes


• severe sleepiness


• shortness of breath


• slow or irregular heartbeat


• unusual tiredness

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

• Abdominal or stomach pain


• agitation


• anxiety


• constipation


• cough


• diarrhea


• discouragement


• drowsiness


• dry mouth


• feeling of warmth


• feeling sad or empty


• feeling unusually cold


• fever


• general feeling of discomfort or illness


• headache


• heartburn


• irritability


• itching of the skin


• joint pain


• loss of appetite


• loss of interest or pleasure


• loss of strength or weakness


• muscle aches and pains


• nausea


• nervousness


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


• restlessness


• runny nose


• shivering


• skin rash


• sleepiness or unusual drowsiness


• sore throat


• stuffy nose


• sweating


• tiredness


• trouble concentrating


• unusual feeling of excitement


• weakness

Less common or rare

• Abnormal dreams


• appetite decreased


• back pain


• bladder pain


• blistering, crusting, irritation, itching, or reddening of the skin


• bloody or cloudy urine


• body aches or pain


• change in hearing


• clamminess


• cold flu-like symptoms


• confusion


• cough producing mucus


• cracked, dry, or scaly skin


• decreased interest in sexual intercourse


• difficult, burning, or painful urination


• difficulty with moving


• disturbance in attention


• ear congestion


• ear drainage


• earache or pain in ear


• excessive gas


• fall


• false or unusual sense of well-being


• feeling hot


• feeling jittery


• flushing or redness of the skin


• general feeling of bodily discomfort


• goosebumps


• headache, severe and throbbing


• hoarseness


• hot flashes


• inability to have or keep an erection


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


• joint sprain


• joint stiffness


• joint swelling


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


• loss of voice


• lower back or side pain


• muscle aching or cramping


• muscle injury


• muscle pain or stiffness


• muscle spasms or twitching


• nasal congestion


• neck pain


• night sweats


• pain


• pain in the limbs


• pain or tenderness around the eyes and cheekbones


• pain, swelling, or redness in the joints


• skin discoloration


• swelling


• swelling of the hands, ankles, feet, or lower legs


• tightness of the chest


• trouble in holding or releasing urine


• trouble with sleeping


• troubled breathing


• weight increased or decreased

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Gooseflesh


• high blood pressure


• increased sweating


• increased yawning


• shivering or trembling


• unusually large pupils

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: FusePaq Synapryn side effects (in more detail)

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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 FusePaq Synapryn resources

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

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Fuzeon Injection

enfuvirtide

Dosage Form: injection - kit
FULL PRESCRIBING INFORMATION

Indications and Usage for Fuzeon Injection

FUZEON® in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

This indication is based on results from two controlled studies of 48 weeks duration. Subjects enrolled were treatment-experienced adults; many had advanced disease. There are no studies of FUZEON in antiretroviral naive subjects.

Fuzeon Injection Dosage and Administration

Adults

The recommended dose of FUZEON is 90 mg (1 mL) twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site, and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected near any anatomical areas where large nerves course close to the skin, such as near the elbow, knee, groin or the inferior or medial section of the buttocks, skin abnormalities, including directly over a blood vessel, into moles, scar tissue, bruises, or near the navel, surgical scars, tattoos or burn sites. Additional detailed information regarding the administration of FUZEON is described in the Fuzeon Injection Instructions.

Pediatric Patients

Insufficient data are available to establish a dose recommendation of FUZEON in pediatric patients below the age of 6 years. In pediatric patients 6 years through 16 years of age, the recommended dosage of FUZEON is 2 mg/kg twice daily up to a maximum dose of 90 mg twice daily injected subcutaneously into the upper arm, anterior thigh or abdomen. Each injection should be given at a site different from the preceding injection site and only where there is no current injection site reaction from an earlier dose. FUZEON should not be injected into moles, scar tissue, bruises or the navel. Table 1 contains dosing guidelines for FUZEON based on body weight. Weight should be monitored periodically and the FUZEON dose adjusted accordingly.

Table 1 Pediatric Dosing Guidelines

Weight		Dose per bid Injection (mg/dose)	Injection Volume (90 mg enfuvirtide per mL)
Kilograms (kg)	Pounds (lbs)
11.0 to 15.5	24 to 34	27	0.3 mL
15.6 to 20.0	>34 to 44	36	0.4 mL
20.1 to 24.5	>44 to 54	45	0.5 mL
24.6 to 29.0	>54 to 64	54	0.6 mL
29.1 to 33.5	>64 to 74	63	0.7 mL
33.6 to 38.0	>74 to 84	72	0.8 mL
38.1 to 42.5	>84 to 94	81	0.9 mL
≥42.6	>94	90	1.0 mL

Directions for Use

For more detailed instructions, see Fuzeon Injection Instructions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

Subcutaneous Administration

FUZEON must only be reconstituted with 1.1 mL of Sterile Water for Injection provided in the Convenience Kit. After adding sterile water, the vial should be gently tapped for 10 seconds and then gently rolled between the hands to avoid foaming and to ensure all particles of drug are in contact with the liquid and no drug remains on the vial wall. The vial should then be allowed to stand until the powder goes completely into solution, which could take up to 45 minutes. Reconstitution time can be reduced by gently rolling the vial between the hands until the product is completely dissolved. Before the solution is withdrawn for administration, the vial should be inspected visually to ensure that the contents are fully dissolved in solution, and that the solution is clear, colorless and without bubbles or particulate matter. If the FUZEON is foamy or jelled, allow more time for it to dissolve. If there is evidence of particulate matter, the vial must not be used and should be returned to the pharmacy.

FUZEON contains no preservatives. Once reconstituted, FUZEON should be injected immediately or kept refrigerated in the original vial until use. Reconstituted FUZEON must be used within 24 hours. The subsequent dose of FUZEON can be reconstituted in advance and must be stored in the refrigerator in the original vial and used within 24 hours. Refrigerated reconstituted solution should be brought to room temperature before injection and the vial should be inspected visually again to ensure that the contents are fully dissolved in solution and that the solution is clear, colorless, and without bubbles or particulate matter.

A vial is suitable for single use only; unused portions must be discarded (see Fuzeon Injection Instructions).

Patients should contact their healthcare provider for any questions regarding the administration of FUZEON. Information about the self-administration of FUZEON may also be obtained by calling the toll-free number 1-877-4-FUZEON (1-877-438-9366) or at the FUZEON website, www.FUZEON.com. Patients should be taught to recognize the signs and symptoms of injection site reactions and instructed when to contact their healthcare provider about these reactions.

Dosage Forms and Strengths

Lyophilized powder for injection: 108 mg enfuvirtide per vial

Contraindications

FUZEON is contraindicated in patients with known hypersensitivity to FUZEON or any of its components [see Warnings and Precautions (5.4)].

Warnings and Precautions

Local Injection Site Reactions (ISRs)

The majority of subjects (98%) receiving FUZEON in randomized, controlled, open-label, multicenter clinical trials had at least one local injection site reaction; ISRs occurred throughout treatment with FUZEON. Manifestations may include pain and discomfort, induration, erythema, nodules and cysts, pruritus, and ecchymosis [see Adverse Reactions (6)]. Reactions are often present at more than one injection site. Patients must be familiar with the Fuzeon Injection Instructions in order to know how to inject FUZEON appropriately and how to monitor carefully for signs or symptoms of cellulitis or local infection.

Administration with Biojector® 2000

Nerve pain (neuralgia and/or paresthesia) lasting up to 6 months associated with administration at anatomical sites where large nerves course close to the skin, bruising and hematomas have occurred with use of the Biojector 2000 needle-free device for administration of FUZEON. Patients receiving anticoagulants or persons with hemophilia, or other coagulation disorders, may have a higher risk of post-injection bleeding.

Pneumonia

An increased rate of bacterial pneumonia was observed in subjects treated with FUZEON in the Phase 3 clinical trials compared to the control arm. The incidence of pneumonia was 2.7% or 3.2 events/100 patient-years in subjects receiving FUZEON+background regimen. On analysis of all diagnoses of pneumonia (pneumonia, bacterial pneumonia, bronchopneumonia, and related terms) in T20-301 and T20-302, an increased rate of bacterial pneumonia was observed in subjects treated with FUZEON compared to the control arm (6.9%, 6.7 pneumonia events per 100 patient-years versus 0.6 events per 100 patient-years, respectively). Approximately half of the study subjects with pneumonia required hospitalization. Three subject deaths in the FUZEON arm were attributed to pneumonia; all three had serious concomitant AIDS-related illnesses that contributed to their deaths. Risk factors for pneumonia included low initial CD4 lymphocyte count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease. It is unclear if the increased incidence of pneumonia was related to FUZEON use. However, because of this finding, patients with HIV-1 infection should be carefully monitored for signs and symptoms of pneumonia, especially if they have underlying conditions which may predispose them to pneumonia. Risk factors for pneumonia included low initial CD4 cell count, high initial viral load, intravenous drug use, smoking, and a prior history of lung disease.

Hypersensitivity Reactions

Systemic hypersensitivity reactions have been associated with FUZEON therapy and may recur on re-challenge. Hypersensitivity reactions have occurred in <1% of subjects studied and have included combinations of: rash, fever, nausea and vomiting, chills, rigors, hypotension, and/or elevated serum liver transaminases. Other adverse events that may be immune mediated and have been reported in subjects receiving FUZEON include primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre syndrome. Patients developing signs and symptoms suggestive of a systemic hypersensitivity reaction should discontinue FUZEON and should seek medical evaluation immediately. Therapy with FUZEON should not be restarted following systemic signs and symptoms consistent with a hypersensitivity reaction. Risk factors that may predict the occurrence or severity of hypersensitivity to FUZEON have not been identified.

Non-HIV Infected Individuals

There is a theoretical risk that FUZEON use may lead to the production of anti-enfuvirtide antibodies which cross react with HIV gp41. This could result in a false positive HIV test with an ELISA assay; a confirmatory western blot test would be expected to be negative. FUZEON has not been studied in non-HIV infected individuals.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FUZEON. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP] or tuberculosis), which may necessitate further evaluation and treatment.

Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections:

• Administration with Biojector® 2000 [see Warnings and Precautions (5.2)]


• Pneumonia [see Warnings and Precautions (5.3)]


• Hypersensitivity Reactions [see Warnings and Precautions (5.4)]

Clinical Trials Experience

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

The overall safety profile of FUZEON is based on 2131 subjects who received at least 1 dose of FUZEON during various clinical trials. This includes 2051 adults, 658 of whom received the recommended dose for greater than 48 weeks, and 63 pediatric subjects.

Assessment of treatment-emergent adverse events is based on the pooled data from the two randomized, controlled, open-label, multicenter trials in treatment-experienced subjects, T20-301 (TORO 1) and T20-302 (TORO 2).

Local Injection Site Reactions

Local injection site reactions were the most frequent adverse events associated with the use of FUZEON. In T20-301 and T20-302, 98% of subjects had at least one local injection site reaction (ISR). A total of 7% of subjects discontinued treatment with FUZEON because of ISRs (4%) or difficulties with injecting FUZEON (3%) such as injection fatigue and inconvenience. Eighty-five percent of subjects experienced their first ISR during the initial week of treatment; ISRs continued to occur throughout treatment with FUZEON. For most subjects the severity of signs and symptoms associated with ISRs did not change during the 48 weeks of treatment. The majority of ISRs were associated with erythema, induration, the presence of nodules or cysts, and mild to moderate pain at the injection site (Table 2). In addition, the average duration of individual ISRs was between three and seven days in 41% of subjects and more than seven days in 24% of subjects. Also, the numbers of ISRs per subject at any one time was between six to 14 ISRs in 26% of subjects and more than 14 ISRs in 1.3% of subjects. Infection at the injection site (including abscess and cellulitis) was reported in 1.7% of adult subjects.

Table 2 Summary of Individual Signs/Symptoms Characterizing Local Injection Site Reactions to Enfuvirtide in Studies T20-301 and T20-302 Combined (% of Subjects) Through 48 Weeks

	N=663
Event Category	Any Severity Grade	% of Subjects with Grade 3 Reactions	% of Subjects with Grade 4 Reactions
* Grade 3 = severe pain requiring prescription non-topical analgesics or limiting usual activities. Grade 4 = severe pain requiring hospitalization or prolongation of hospitalization, resulting in death, or persistent or significant disability/incapacity, or life-threatening, or medically significant. † Grade 3 = refractory to topical treatment or requiring oral or parenteral treatment. Grade 4 = not applicable.
Pain/Discomfort *	96%	11%	0%
Induration	90%	39% >25 but <50 mm	18% ≥50 mm
Erythema	91%	22% >50 but <85 mm	10% ≥85 mm
Nodules and Cysts	80%	23% >3 cm average diameter	0.2% Draining
Pruritus †	65%	3%	NA
Ecchymosis	52%	5% >3 but ≤5 cm	2% >5 cm

Other Adverse Events

In T20-301 and T20-302, after study week 8, subjects on background alone who met protocol defined criteria for virological failure were permitted to revise their background regimens and add FUZEON. Exposure on FUZEON+background was 557 patient-years, and to background alone 162 patient-years. Due to this difference in exposure, safety results are expressed as the number of patients with an adverse event per 100 patient-years of exposure. For FUZEON+background, adverse events are also displayed by percent of subjects.

The events most frequently reported in subjects receiving FUZEON+background regimen, excluding ISRs, were diarrhea (38 per 100 patient-years or 31.7%), nausea (27 per 100 patient-years or 22.8%), and fatigue (24 per 100 patient-years or 20.2%). These events were also commonly observed in subjects that received background regimen alone: diarrhea (73 per 100 patient-years), nausea (50 per 100 patient-years), and fatigue (38 per 100 patient-years).

Treatment-emergent adverse events, regardless of causality and excluding ISRs, from Phase 3 studies are summarized for adult subjects, in Table 3. Any Grade 2 or above events occurring at ≥2 percent of subjects and at a higher rate in subjects treated with FUZEON are summarized in Table 3; events that occurred at a higher rate in the control arms are not displayed.

Rates of adverse events for subjects who switched to FUZEON after virological failure were similar.

Table 3 Rates of Treatment-Emergent Adverse Events* (≥Grade 2) Reported in ≥2% of Subjects Treated with FUZEON† (Pooled Studies T20-301/T20-302 at 48 Weeks)

Adverse Event (by System Organ Class)	FUZEON+Back-ground Regimen (N=663)	FUZEON+Back-ground Regimen (N=663)	Background Regimen (N=334)
	663 subjects total	557 total patient-years	162 total patient-years
	% frequency	rate/100 patient-years	rate/100 patient-years
* Excludes Injection Site Reactions † Events listed occurred more frequently in subjects treated with FUZEON (based on rates/100 patient-years).
Weight Decreased	6.6%	7.9	6.2
Sinusitis	6.0%	7.2	4.9
Abdominal Pain	3.9%	4.7	3.7
Cough	3.9%	4.7	2.5
Herpes Simplex	3.5%	4.1	3.7
Appetite Decreased	3.2%	3.8	2.5
Pancreatitis	3.0%	3.6	2.5
Pain in Limb	2.9%	3.4	3.1
Pneumonia (see text below)	2.7%	3.2	0.6
Myalgia	2.7%	3.2	1.2
Influenza-Like Illness	2.4%	2.9	1.9
Folliculitis	2.4%	2.9	2.5
Anorexia	2.3%	2.7	1.9
Dry Mouth	2.1%	2.5	1.9
Conjunctivitis	2.0%	2.3	1.9

Less Common Events

The following adverse events have been reported in 1 or more subjects; however, a causal relationship to FUZEON has not been established.

Immune System Disorders: worsening abacavir hypersensitivity reaction

Renal and Urinary Disorders: glomerulonephritis; tubular necrosis; renal insufficiency; renal failure (including fatal cases)

Blood and Lymphatic Disorders: thrombocytopenia; neutropenia; fever; lymphadenopathy

Endocrine and Metabolic: hyperglycemia

Infections: sepsis; herpes simplex

Nervous System Disorders: taste disturbance; Guillain-Barre syndrome (fatal); sixth nerve palsy; peripheral neuropathy

Cardiac Disorders: unstable angina pectoris

Gastrointestinal Disorders: constipation; abdominal pain upper

General: asthenia

Hepatobiliary Disorders: toxic hepatitis; hepatic steatosis

Investigations: increased amylase; increased lipase; increased AST; increased GGT; increased triglycerides

Psychiatric Disorders: insomnia; depression; anxiety; suicide attempt

Respiratory, Thoracic, and Mediastinal Disorders: pneumopathy; respiratory distress; cough

Skin and Subcutaneous Tissue Disorders: pruritus

Laboratory Abnormalities

Table 4 shows the treatment-emergent laboratory abnormalities that occurred in at least 2 subjects per 100 patient-years and more frequently in those receiving FUZEON+background regimen than background regimen alone from T20-301 and T20-302.

Table 4 Treatment-Emergent Laboratory Abnormalities in ≥2% of Subjects Receiving FUZEON* (Pooled Studies T20-301 and T20-302 at 48 Weeks)

Laboratory Parameters	Grading	FUZEON+Back-ground Regimen (N=663)	FUZEON+Back-ground Regimen (N=663)	Background Regimen (N=334)
		663 subjects total	557 total patient-years	162 total patient-years
		% frequency	rate/100 patient-years	rate/100 patient-years
* Events listed occurred more frequently in subjects treated with FUZEON (based on rates/100 patient-years).
Eosinophilia
1-2 X ULN (0.7 × 109/L)	0.7-1.4 × 109/L	9.1%	10.8	3.7
>2 X ULN (0.7 × 109/L)	>1.4 × 109/L	1.8%	2.2	1.8
ALT
Grade 3	>5-10 × ULN	4.1%	4.8	4.3
Grade 4	>10 × ULN	1.2%	1.4	1.2
Creatine Phosphokinase (U/L)
Grade 3	>5-10 × ULN	6.9%	8.3	8.0
Grade 4	>10 × ULN	2.6%	3.1	8.6

Adverse Events in Pediatric Patients

FUZEON has been studied in 63 pediatric subjects 5 through 16 years of age with duration of FUZEON exposure ranging from 1 dose to 134 weeks. Adverse experiences seen during clinical trials were similar to those observed in adult subjects, although infections at site of injection (cellulitis or abscess) were more frequent in adolescents than in adults, with 4 events occurring in 3 of 28 (11%) subjects.

Drug Interactions

See also Clinical Pharmacology (12.3)

Potential for FUZEON to Affect Other Drugs

Based on the results from an in vitro human microsomal study, enfuvirtide is not an inhibitor of CYP450 enzymes. In an in vivo human metabolism study (N=12), FUZEON at the recommended dose of 90 mg twice daily did not alter the metabolism of CYP3A4, CYP2D6, CYP1A2, CYP2C19 or CYP2E1 substrates.

Potential for Other Drugs to Affect Enfuvirtide

Based on the available data, co-administration of FUZEON and other drugs which are inducers or inhibitors of CYP450 is not expected to alter the pharmacokinetics of enfuvirtide. No dose adjustments are needed when FUZEON is co-administered with other antiretroviral and non-antiretroviral drugs.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

Reproduction studies have been performed in rats and rabbits at doses up to 27 times and 3.2 times the adult human dose on a m2 basis and have revealed no evidence of impaired fertility or harm to the fetus due to enfuvirtide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to FUZEON and other antiretroviral drugs, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Nursing Mothers

The Centers for Disease Control and Prevention recommends that HIV-infected mothers not breast-feed their infants to avoid the risk of postnatal transmission of HIV. It is not known whether enfuvirtide is excreted in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving FUZEON.

Studies where radio-labeled 3H-enfuvirtide was administered to lactating rats indicated that radioactivity was present in the milk. It is not known whether the radioactivity in the milk was from radio-labeled enfuvirtide or from radio-labeled metabolites of enfuvirtide (i.e., amino acids and peptide fragments).

Pediatric Use

The safety and pharmacokinetics of FUZEON have been evaluated in the age groups of 6 to 16 years of age supported by evidence from adequate and well-controlled studies of FUZEON in adults. Limited efficacy data are available in pediatric subjects 6 years of age and older [see Clinical Pharmacology (12.3)].

Sixty-three HIV-1 infected pediatric subjects ages 5 through 16 years have received FUZEON in two open-label, single-arm clinical trials. Adverse experiences, including ISRs, were similar to those observed in adult subjects.

T20-204 was an open-label, multicenter trial that evaluated the safety and antiviral activity of FUZEON in treatment-experienced pediatric subjects. Eleven subjects from 6 to 12 years were enrolled (median age of 9 years). Median baseline CD4 cell count was 495 cells/µL and the median baseline HIV-1 RNA was 4.6 log10 copies/mL.

Ten of the 11 study subjects completed 48 weeks of chronic therapy. At week 48, 6/11 (55%) subjects had ≥1 log10 decline in HIV-1 RNA and 4/11 (36%) subjects were below 400 copies/mL of HIV-1 RNA. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.48 log10 copies/mL and +122 cells/µL, respectively.

T20-310 was an open-label, multicenter trial that evaluated the pharmacokinetics, safety, and antiviral activity of FUZEON in treatment-experienced pediatric subjects and adolescents. Fifty-two subjects from 5 through 16 years were enrolled (median age of 12 years). Median baseline CD4 cell count was 117 cells/µL and the median baseline HIV-1 RNA was 5.0 log10 copies/mL.

Thirty-two of the 52 study subjects completed 48 weeks of chronic therapy. At week 48, 17/52 (33%) of subjects had ≥1 log10 decline in HIV-1 RNA, 11/52 (21%) of subjects were below 400 copies/mL of HIV-1 RNA and 5/52 (10%) were below 50 copies/mL. The median changes from baseline (for the As Treated population) in HIV-1 RNA and CD4 cell count were -1.17 log10 copies/mL and +106 cells/µL, respectively.

Geriatric Use

Clinical studies of FUZEON did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of FUZEON in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Use in Patients with Hepatic Impairment

No dose adjustments of enfuvirtide are needed in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Use in Patients with Renal Impairment

No dose adjustments of enfuvirtide are needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

Overdosage

There are no reports of human experience of acute overdose with FUZEON. The highest dose administered to 12 subjects in a clinical trial was 180 mg as a single dose subcutaneously. There is no specific antidote for overdose with FUZEON. Treatment of overdose should consist of general supportive measures.

Fuzeon Injection Description

FUZEON (enfuvirtide) is an inhibitor of the fusion of HIV-1 with CD4 cells. Enfuvirtide is a linear 36-amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide. It is composed of naturally occurring L-amino acid residues.

Enfuvirtide is a white to off-white amorphous solid. It has negligible solubility in pure water and the solubility increases in aqueous buffers (pH 7.5) to 85-142 g/100 mL. The empirical formula of enfuvirtide is C204H301N51O64, and the molecular weight is 4492. It has the following primary amino acid sequence:

CH3CO - Tyr - Thr - Ser - Leu - Ile - His - Ser - Leu - Ile - Glu - Glu - Ser - Gln - Asn - Gln - Gln - Glu - Lys - Asn - Glu - Gln - Glu - Leu - Leu - Glu - Leu - Asp - Lys - Trp - Ala - Ser - Leu - Trp - Asn - Trp - Phe - NH2 and the following structural formula:

The drug product, FUZEON (enfuvirtide) for Injection, is a white to off-white, sterile, lyophilized powder. Each single-use vial contains 108 mg of enfuvirtide for the delivery of 90 mg. Prior to subcutaneous administration, the contents of the vial are reconstituted with 1.1 mL of Sterile Water for Injection giving a volume of approximately 1.2 mL to provide the delivery of 1 mL of the solution. Each 1 mL of the reconstituted solution contains approximately 90 mg of enfuvirtide with approximate amounts of the following excipients: 22.55 mg of mannitol, 2.39 mg of sodium carbonate (anhydrous), and sodium hydroxide and hydrochloric acid for pH adjustment as needed. The reconstituted solution has an approximate pH of 9.0.

Fuzeon Injection - Clinical Pharmacology

Mechanism of Action

Enfuvirtide is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacokinetics

The pharmacokinetic properties of enfuvirtide were evaluated in HIV-1 infected adult and pediatric subjects.

Absorption

Following a 90-mg single subcutaneous injection of FUZEON into the abdomen in 12 HIV-1 infected subjects, the mean (±SD) Cmax was 4.59 ± 1.5 µg/mL, AUC was 55.8 ± 12.1 µg∙h/mL and the median Tmax was 8 hours (ranged from 3 to 12 h). The absolute bioavailability (using a 90-mg intravenous dose as a reference) was 84.3% ± 15.5%. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean (±SD) steady-state Cmax was 5.0 ± 1.7 µg/mL, Ctrough was 3.3 ± 1.6 µg/mL, AUC0-12h was 48.7 ± 19.1 µg∙h/mL, and the median Tmax was 4 hours (ranged from 4 to 8 h).

Absorption of the 90-mg dose was comparable when injected into the subcutaneous tissue of the abdomen, thigh or arm.

Distribution

The mean (±SD) steady-state volume of distribution after intravenous administration of a 90-mg dose of FUZEON (N=12) was 5.5 ± 1.1 L.

Enfuvirtide is approximately 92% bound to plasma proteins in HIV-infected plasma over a concentration range of 2 to 10 µg/mL. It is bound predominantly to albumin and to a lower extent to α-1 acid glycoprotein.

The CSF levels of enfuvirtide (measured from 2 hours to 18 hours after administration of enfuvirtide) in 4 HIV-infected subjects were below the limit of quantification (0.025 µg/mL).

Metabolism/Elimination

As a peptide, enfuvirtide is expected to undergo catabolism to its constituent amino acids, with subsequent recycling of the amino acids in the body pool.

Mass balance studies to determine elimination pathway(s) of enfuvirtide have not been performed in humans.

In vitro studies with human microsomes and hepatocytes indicate that enfuvirtide undergoes hydrolysis to form a deamidated metabolite at the C-terminal phenylalanine residue, M3. The hydrolysis reaction is not NADPH dependent. The M3 metabolite is detected in human plasma following administration of enfuvirtide, with an AUC ranging from 2.4% to 15% of the enfuvirtide AUC.

Following a 90-mg single subcutaneous dose of enfuvirtide (N=12) the mean ±SD elimination half-life of enfuvirtide is 3.8 ± 0.6 h and the mean ±SD apparent clearance was 24.8 ± 4.1 mL/h/kg. Following 90-mg twice daily dosing of FUZEON subcutaneously in combination with other antiretroviral agents in 11 HIV-1 infected subjects, the mean ±SD apparent clearance was 30.6 ± 10.6 mL/h/kg.

Special Populations

Hepatic Impairment

Formal pharmacokinetic studies of enfuvirtide have not been conducted in subjects with hepatic impairment.

Renal Impairment

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is not affected in patients with creatinine clearance greater than 35 mL/min. The results of a renal impairment study indicate clearance of enfuvirtide was reduced by 38% in subjects with severe renal impairment (CL = 11 – 35 mL/min; n = 4) and by 14 - 28% in subjects with end-stage renal disease maintained on dialysis (n = 8) compared to subjects with normal renal function (CL >80 mL/min; n = 8). Hemodialysis did not significantly alter enfuvirtide clearance.

No dose adjustment is recommended for patients with impaired renal function.

Gender and Weight

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide is 20% lower in females than males after adjusting for body weight.

Enfuvirtide clearance decreases with decreased body weight irrespective of gender. Relative to the clearance of a 70-kg male, a 40-kg male will have 20% lower clearance and a 110-kg male will have a 26% higher clearance. Relative to a 70-kg male, a 40-kg female will have a 36% lower clearance and a 110-kg female will have the same clearance.

No dose adjustment is recommended for weight or gender.

Race

Analysis of plasma concentration data from subjects in clinical trials indicated that the clearance of enfuvirtide was not different in Blacks compared to Caucasians. Other pharmacokinetic studies suggest no difference between Asians and Caucasians after adjusting for body weight.

Pediatric Patients

The pharmacokinetics of enfuvirtide have been studied in 23 pediatric subjects aged 6 through 16 years at a dose of 2 mg/kg. Enfuvirtide pharmacokinetics were determined in the presence of concomitant medications including antiretroviral agents. A dose of 2 mg/kg twice daily (maximum 90 mg twice daily) provided enfuvirtide plasma concentrations similar to those obtained in adult subjects receiving 90 mg twice daily.

In the 23 pediatric subjects receiving the 2 mg/kg twice daily dose, the mean ±SD steady-state AUC was 56.3 ± 22.3 µg∙h/mL, Cmax was 6.3 ± 2.4 µg/mL, Ctrough was 3.1 ± 1.5 µg/mL, and apparent clearance was 40 ± 17 mL/h/kg [see Use in Specific Populations (8.4)].

Geriatric Patients

The pharmacokinetics of enfuvirtide have not been studied in patients over 65 years of age.

Drug Interactions

See also Drug Interactions (7)

Table 5 shows the results of the drug-drug interaction studies conducted between FUZEON and the following drugs: ritonavir, saquinavir/ritonavir, and rifampin.

Table 5 Effect of Ritonavir, Saquinavir/Ritonavir, and Rifampin on the Steady-State Pharmacokinetics of Enfuvirtide (90 mg bid)*

Coadministered Drug	Dose of Coadministered Drug	N	% Change of Enfuvirtide Pharmacokinetic Parameters†‡ (90% CI)
			Cmax	AUC	Ctrough
* All studies were performed in HIV-1+ subjects using a sequential crossover design. † ↑= Increase; ↓ = Decrease; ‡ No interactions were clinically significant.
Ritonavir	200 mg, q12h, 4 days	12	↑24 (↑9 to ↑41)	↑22 (↑8 to ↑37)	↑14 (↑2 to ↑28)
Saquinavir/ Ritonavir	1000/100 mg, q12h, 4 days	12		↑14 (↑5 to ↑24)	↑26 (↑17 to↑35)
Rifampin	600 mg, qd, 10 days	12			↓15 (↓22 to ↓7)

Microbiology

Mechanism of Action

Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes. Enfuvirtide binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes.

Antiviral Activity in Cell Culture

The antiviral activity of enfuvirtide was assessed by infecting different CD4 cell types with laboratory and clinical isolates of HIV-1. The geometric mean EC50 value for baseline clinical isolates was 3.52 nM (ranged from 0.089 to 107 nM; 0.4 to 480 ng/mL) by the cMAGI assay (n=130) and was 57.9 nM (1.56 to 1680 nM; 7 to 7530 ng/mL) by a recombinant phenotypic entry assay (n=627). Enfuvirtide was similarly active in cell culture against clades A, AE, C, D, E, F, and G (geometric mean EC50 value was 7.7 nM; range 3.9 to 28.6 nM), and R5, X4, and dual tropic viruses. Enfuvirtide has no activity against HIV-2.

Enfuvirtide exhibited additive to synergistic effects in cell culture assays when combined with individual members of various antiretroviral classes, including lamivudine, zidovudine, indinavir, nelfinavir, and efavirenz.

Drug Resistance

HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in cell culture. Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36 to 38 of the HIV-1 envelope glycoprotein gp41. Phenotypic analysis of site-directed mutants in positions 36 to 38 in an HIV-1 molecular clone showed a 5-fold to 684-fold decrease in susceptibility to enfuvirtide.

In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing a FUZEON containing regimen. Posttreatment HIV-1 virus from 277 subjects experiencing protocol defined virological failure at 48 weeks exhibited a median decrease in susceptibility to enfuvirtide of 33.4-fold (range 0.4-6318-fold) relative to their respective baseline virus. Of these, 249 had decreases in susceptibility to enfuvirtide of greater than 4-fold and all but 3 of those 249 exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36 to 45. Substitutions in this region were observed with decreasing frequency at amino acid positions 38, 43, 36, 40, 42, and 45. Mutations or polymorphisms in other regions of the envelope (e.g., the HR2 region or those yet to be identified) as well as co-receptor usage and density may affect susceptibility to enfuvirtide.

Cross-resistance

HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors (NRTI), non-nucleoside analogue reverse transcriptase inhibitors (NNRTI), and protease inhibitors (PI) were susceptible to enfuvirtide in cell culture.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

FusePaq Fanatrex

Generic Name: gabapentin (Oral route)

gab-a-PEN-tin

Commonly used brand name(s)

In the U.S.

• FusePaq Fanatrex


• Gabarone


• Gralise


• Neurontin

Available Dosage Forms:

• Capsule


• Suspension


• Tablet


• Solution

Therapeutic Class: Anticonvulsant

Chemical Class: Gamma Aminobutyric Acid (class)

Uses For FusePaq Fanatrex

Gabapentin is used to help control partial seizures (convulsions) in the treatment of epilepsy. This medicine cannot cure epilepsy and will only work to control seizures for as long as you continue to take it.

Gabapentin is also used in adults to manage a condition called postherpetic neuralgia, which is pain that occurs after “shingles.”

Gabapentin extended-release tablets is used to treat a condition called Restless Legs Syndrome (RLS). RLS is a neurologic disorder that affects sensation and movement in the legs to feel uncomfortable. This results in an irresistible feeling of wanting to move your legs to make them comfortable.

Gabapentin is an anticonvulsant. It increases the amount of a chemical called gamma-aminobutyric acid (GABA) in the brain. It is felt that some epileptic seizures occur when there are low levels of GABA in the brain. By increasing the amount of GABA, gabapentin reduces the number of seizures.

Gabapentin also works to relieve pain for certain conditions in the nervous system. It is not used for routine pain caused by minor injuries or arthritis.

This medicine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although this use is not included in product labeling, gabapentin is used in certain patients with the following medical condition:

• Diabetic peripheral neuropathy.

Before Using FusePaq Fanatrex

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

Allergies

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

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of gabapentin for treating partial seizures in children. However, safety and efficacy have not been established in children younger than 3 years of age.

Appropriate studies have not been performed on the relationship of age to the effects of gabapentin for treating postherpetic neuralgia and Restless Legs Syndrome in children. 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 gabapentin in the elderly. However, elderly patients are more likely to have unwanted effects (e.g., problems with balance or walking, swelling in the feet or legs) and age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving gabapentin.

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 taking this medicine, 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 this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Ketorolac


• Naproxen

Using this medicine 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.

• Aluminum Carbonate, Basic


• Aluminum Hydroxide


• Aluminum Phosphate


• Dihydroxyaluminum Aminoacetate


• Dihydroxyaluminum Sodium Carbonate


• Ginkgo


• Magaldrate


• Magnesium Carbonate


• Magnesium Hydroxide


• Magnesium Oxide


• Magnesium Trisilicate


• Morphine


• Morphine Sulfate Liposome

Interactions with Food/Tobacco/Alcohol

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

Other Medical Problems

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

• Cancer or tumors, history of or


• Depression, history of or


• Mental illness, history of—Use with caution. May make these conditions worse.

• Kidney disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Kidney impairment, severe or


• Undergoing kidney dialysis—Should not be used in patients with these conditions.

Proper Use of gabapentin

This section provides information on the proper use of a number of products that contain gabapentin. It may not be specific to FusePaq Fanatrex. Please read with care.

Take this medicine only as directed by your doctor, to help your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. To do so may increase the chance of side effects.

This medicine comes with a Medication Guide. It is very important that you read and understand this information. Be sure to ask your doctor about anything you do not understand.

Gabapentin may be taken with or without food. However, if your doctor tells you to take the medicine a certain way, take it exactly as directed.

Do not use the Horizant® extended-release tablets if you are required to sleep during daytime and remain awake at night.

For patients with epilepsy who take gabapentin three times per day, do not allow more than 12 hours to pass between any 2 doses. The medicine works best if a constant amount is in the blood.

If you or your child have trouble swallowing capsules, talk to your doctor about using the tablet or solution form. This medicine may also be given as a combination with any of the forms, such as tablets with solution.

You may break the scored Neurontin® tablets into two pieces, but make sure you or your child use the second half of the tablet as the next dose. Ask your doctor or pharmacist if you have any questions.

Swallow the Gralise® tablets or the Horizant® extended-release tablets whole. Do not break, crush, or chew them. The Gralise® tablets should be taken with the evening meal. The Horizant® extended-release tablets should be taken with food at about 5 PM.

Measure the oral liquid using a marked measuring spoon, oral syringe, or medicine cup. The average household teaspoon may not hold the right amount of liquid.

Gabapentin may be used together with other seizure medicines. Keep using all of your medicines unless your doctor tells you to stop.

If you take an antacid (such as Di-Gel®, Gaviscon®, Gelusil®, Maalox® or Mylanta®), wait at least 2 hours before taking gabapentin.

Use only the brand of this medicine that your doctor prescribed. Different brands may not work the same way. Take the Horizant® extended-release tablets only for Restless Legs Syndrome. The safety and effectiveness of the extended-release tablet for epilepsy have not been established.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (capsules, solution, and tablets):
  
  • For epilepsy:
    
    • Adults and teenagers 12 years of age and older—At first, 300 milligrams (mg) three times per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 1800 mg per day.
    
    
    • Children 3 to 12 years of age—Dose is based on body weight and must be determined by your doctor. The starting dose is 10 to 15 milligrams (mg) per kilogram (kg) of body weight per day, divided into three doses. Your doctor may adjust your dose as needed. The usual dose for children 5 years of age and older is 25 to 35 mg per kg of body weight per day, divided into three doses. The usual dose for children 3 and 4 years of age is 40 mg per kg of body weight per day, divided into three doses.
    
    
    • Children younger than 3 years of age—Use and dose must be determined by your doctor.
    
    
  
  
  • For postherpetic neuralgia:
    
    • Adults— At first, 300 milligrams (mg) taken as a single dose on day 1. On day 2, 300 mg two times per day. On day 3, 300 mg three times per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 1800 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  


• For oral dosage form (extended-release tablet):
  
  • For Restless Legs Syndrome:
    
    • Adults—600 milligrams (mg) once a day to be taken with food at about 5 PM. Your doctor may adjust your dose as needed. However, the dose is usually not more than 1200 mg per day.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you missed taking the dose of Horizant® extended-release tablets at the recommended time, take the next dose at about 5 PM the following day.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

You should store the oral liquid in the refrigerator. Do not freeze.

Precautions While Using FusePaq Fanatrex

It is very important that your doctor check the progress of you or your child at regular visits, especially for the first few months you take gabapentin. This is necessary to allow dose adjustments and to check for any unwanted effects. Blood tests may also be needed to check for unwanted effects.

It is important to tell your doctor if you become pregnant. Your doctor may want you to join the North American Antiepileptic Drug Pregnancy Registry. The registry is used by pregnant patients who are taking this medicine.

This medicine may cause some people to be agitated, irritable, or display other abnormal behaviors, such as feeling sad or hopeless, getting upset easily, or feeling nervous, restless, or hostile. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, tell your doctor right away.

This medicine will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever, allergies, or colds; sedatives, tranquilizers, or sleeping medicine; prescription pain medicine or narcotics; other medicines for seizures (e.g., barbiturates); muscle relaxants; or anesthetics, including some dental anesthetics. Check with your medical doctor or dentist before taking any of the above while you or your child are using gabapentin.

Gabapentin may cause blurred vision, double vision, clumsiness, unsteadiness, dizziness, drowsiness, sleepiness, or trouble with thinking. Make sure you know how you react to this medicine before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, or able to think or see well. If these side effects are especially bothersome, check with your doctor.

Stop using this medicine and check with your doctor right away if you or your child develop a fever; rash; swollen, painful, or tender lymph glands in the neck, armpit, or groin; unusual bleeding or bruising; or yellow eyes or skin. These may be symptoms of a serious and life-threatening condition called Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Before you have any medical tests, tell the doctor in charge that you or your child are taking gabapentin. The results of certain medical tests may be affected by this medicine.

Do not stop using gabapentin without first checking with your doctor. Stopping the medicine suddenly may cause your seizures to return or to occur more often. Your doctor may want you or your child to gradually reduce the amount you are taking before stopping it completely.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

FusePaq Fanatrex 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 immediately if any of the following side effects occur:

More common

• Clumsiness or unsteadiness


• continuous, uncontrolled, back-and-forth, or rolling eye movements

More common in children

• Aggressive behavior or other behavior problems


• anxiety


• concentration problems and change in school performance


• crying


• depression


• false sense of well-being


• hyperactivity or increase in body movements


• rapidly changing moods


• reacting too quickly, too emotionally, or overreacting


• restlessness


• suspiciousness or distrust

Less common

• Black, tarry stools


• chest pain


• chills


• cough


• depression, irritability, or other mood or mental changes


• fever


• loss of memory


• pain or swelling in the arms or legs


• painful or difficult urination


• shortness of breath


• sore throat


• sores, ulcers, or white spots on the lips or in the mouth


• swollen glands


• unusual bleeding or bruising


• unusual tiredness or weakness

Incidence not known

• Abdominal or stomach pain


• blistering, peeling, or loosening of the skin


• clay-colored stools


• coma


• confusion


• convulsions


• dark urine


• decreased urine output


• diarrhea


• dizziness


• fast or irregular heartbeat


• headache


• increased thirst


• itching


• joint pain


• large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, feet, or sex organs


• loss of appetite


• muscle ache or pain


• nausea


• red skin lesions, often with a purple center


• red, irritated eyes


• skin rash


• unpleasant breath odor


• vomiting of blood


• yellow eyes or skin

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

Symptoms of overdose

• Double vision


• drowsiness


• sluggishness


• slurred speech


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

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

• Blurred vision


• cold or flu-like symptoms


• delusions


• dementia


• hoarseness


• lack or loss of strength


• lower back or side pain


• swelling of the hands, feet, or lower legs


• trembling or shaking

Less common or rare

• Accidental injury


• appetite increased


• back pain


• bloated or full feeling


• body aches or pain


• burning, dry, or itching eyes


• change in vision


• change in walking and balance


• clumsiness or unsteadiness


• congestion


• constipation


• cough producing mucus


• decrease in sexual desire or ability


• dementia


• difficulty with breathing


• dryness of the mouth or throat


• earache


• excess air or gas in the stomach or intestines


• excessive tearing


• eye discharge


• feeling faint, dizzy, or lightheadedness


• feeling of warmth or heat


• flushed, dry skin


• flushing or redness of the skin, especially on the face and neck


• frequent urination


• fruit-like breath odor


• impaired vision


• incoordination


• increased hunger


• increased sensitivity to pain


• increased sensitivity to touch


• increased thirst


• indigestion


• low blood pressure


• nervousness


• noise in the ears


• pain, redness, rash, swelling, or bleeding where the skin is rubbed off


• passing gas


• redness or swelling in the ear


• redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid


• runny nose


• sneezing


• sweating


• tender, swollen glands in the neck


• tightness in the chest


• tingling in the hands and feet


• troubled breathing


• trouble with sleeping


• trouble with swallowing


• trouble with thinking


• twitching


• unexplained weight loss


• voice changes


• vomiting


• weakness or loss of strength


• weight gain


• wheezing

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: FusePaq Fanatrex side effects (in more detail)

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More FusePaq Fanatrex resources

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

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