SUMMARY OF NALTREXONE PELLETS

NAME OF PRODUCT

GPL naltrexone 0.4%, 1.0g Slow Release Naltrexone pellets

QUALITATIVE AND QUANTITATIVE COMPOSITION Each implant (ie one trochar) contains 1 pellets.

PHARMACEUTICAL FORM

Implantable pellet

THERAPEUTIC INDICATIONS

Implant naltrexone is used on patients who are declaring clearly that they wish to cease their opiate dependence on a long-term basis. As an adjunct to prevent relapse in detoxified formerly opioid-dependent patients (who have remained opioid free for at least 7-10 days). Naltrexone is an opioid antagonist with highest affinity for the mµ opioid receptor. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism.

The administration of naltrexone is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology.

Occupation of opioid receptors by naltrexone may block the effects of endogenous opioid peptides. The neurobiological mechanisms responsible for the reduction in alcohol consumption observed in alcohol-dependent patients treated with naltrexone are not entirely understood. However, involvement of the endogenous opioid system is suggested by preclinical data.

Naltrexone blocks the effects of opioids by competitive binding at opioid receptors. This makes the blockade produced potentially surmountable but overcoming full naltrexone blockade by administration of opioids may result in non-opioid receptor mediated symptoms such as histamine release.

Naltrexone is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion.

HYPERLINK “https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009” PHARMACOKINETICS

Absorption

GPL Naltrexone pellets are intended to release over a 10-12 week period when administered subcutaneously. After implantation, the naltrexone plasma concentration time profile is characterized by an initial peak. Levels begin to decline slowly after dosing, with measurable levels for greater than 10-12weeks.

Distribution

In vitro data demonstrate that naltrexone plasma protein binding is low (21%).

Metabolism

Naltrexone is extensively metabolised in humans. Production of the primary metabolite, 6β-naltrexol, is mediated by dihydrodiol dehydrogenase, a cytosolic family of enzymes. The cytochrome P450 system is not involved in naltrexone metabolism. Two other minor metabolites are 2-hydroxy-3-methoxy-6β-naltrexol and 2-hydroxy-3-methoxy-naltrexone. Naltrexone and its metabolites are also conjugated to form glucuronide products.

Significantly less 6β-naltrexol is generated following subcutaneous administration of naltrexone compared to administration of oral naltrexone due to a reduction in first-pass hepatic metabolism.

Elimination

Elimination of naltrexone and its metabolites occurs primarily via urine, with minimal excretion of unchanged naltrexone.

Race: The effect of race on the pharmacokinetics of naltrexone implants has not been studied.

Paediatrics: The pharmacokinetics of naltrexone have not been evaluated in a paediatric population.

Drug-Drug Interactions

Clinical drug interaction studies with naltrexone implants have not been performed.
Naltrexone antagonizes the effects of opioid-containing medicines, such as cough and cold remedies, antidiarrheal preparations and opioid analgesics.

HYPERLINK “https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009” CLINICAL STUDIES

Multiple studies have demonstrated an increase of adherence to drug and alcohol detox programs with extended release formulations.

The efficacy of naltrexone implants in the treatment of alcohol and various drug addiction was evaluated in a 10 week, placebo-controlled, trial in USA. Subjects were treated with an implantation of 1.0 g Naltrexone. Oral naltrexone was not administered prior to the initial implantation. Psychological support was provided to all subjects on a weekly basis in addition to medication.

Subjects treated with naltrexone 1.0 g implants demonstrated a greater reduction in days of heavy drinking and other substance abuse than those treated with placebo.

In another study published in the British Journal of Psychiatry, 56 patients at an addiction research centre in Norway were given a naltrexone implant for treatment of heroin dependence. Researchers found that study participants who used the naltrexone implant for 180 days had an average of 45 fewer days of heroin use than members of the control group – and 60 fewer days of opioid use than members of the control group.

Similarly, a 2014 systematic review published in the Drug and Alcohol Review examined a variety of research results from 9 studies comparing naltrexone implant treatment to either oral naltrexone or to no treatment at all (a placebo).
Across the 9 studies, naltrexone implants were found to be:

Significantly more effective than oral naltrexone.

Significantly more effective than having no treatment at all.

Since the quality of these studies was evaluated as being “moderate to very low,” more research is still needed to better determine the effectiveness of naltrexone implants. However, the data so far suggests that naltrexone implants appear to improve addiction recovery success compared to taking naltrexone pills and compared to attempting to quit an addiction without any medication help.

HYPERLINK “https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009” INDICATIONS AND USAGE

Treatment with naltrexone implants should be part of a comprehensive management program that includes psychological and psychosocial support.

Naltrexone tablets were initially approved by the FDA in 1985 for the treatment of abuse and addiction of opioids.

Naltrexone in oral and extended release injection forms have been approved by the FDA for the treatment and abuse of alcohol.

Naltrexone implants may be useful for the treatment of alcohol or opioid dependence in patients who are able to abstain from opioid or alcohol in an outpatient setting prior to initiation of treatment.

Patients should not be actively drinking or be on any opioids at the time of initial naltrexone implant administration.

RECOMMENDED DOSING ROUTINE

Naltrexone implants must be administered by a physician.

To prevent occurrence of an acute abstinence syndrome (withdrawal) in patients dependent on opioids, or exacerbation of a pre-existing subclinical abstinence syndrome, opioid-dependent patients, including those being treated for alcohol dependence, must be opioid-free for a minimum of 7–10 days before starting Naltrexone Implant treatment. Since the absence of an opioid drug in the urine is often not sufficient proof that a patient is opioid-free, a naloxone challenge test should be employed if the prescribing physician feels there is a risk of precipitating a withdrawal reaction following administration of Naltrexone Implants. Patients treated for alcohol dependence with Naltrexone Implants should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment with Naltrexone Implants. Precipitated opioid withdrawal has been observed in alcohol-dependent patients in circumstances where the prescriber

It is recommended that a standard implant is inserted with 1 separate syringe loads of 1 pellet making a standard implant dose equal to 1.0g of naltrexone.

Because heroin addiction tends to be a long-term disease it is then recommended to insert one implant every 10 -12 weeks after the first implant. Because of individual variation blood naltrexone monitoring is recommended when possible. Healthcare providers should tailor the length of treatment to individual patients. Naltrexone has been administered to patients who are alcohol dependent for 6 months to 1 year with no additional safety concerns. Many scientists claim that treatment duration should last at least 1 year since this is the amount of time it can take to change the brain’s addiction pathways.

Treatment with Naltrexone should be part of a psychological and psychosocial program.

Risks of Implant Procedures versus Oral naltrexone.

Naltrexone has been available for at least 40 years and has been used clinically since 1973.

Naltrexone has been known to be a potential irritant to tissues for approximately 20 years. The slow release from these implants designed in the USA minimises the irritation to tissues and are experienced with approximately 500 implants inserted in Europe has confirmed a significant allergic response in 3 out of the 500 patients. In one of these patients, immediate surgical removal was required. In two of the patients a good response to anti-allergic drugs (Phenergan and Ranitidine) was observed. It was not necessary in either of these two patients to progress on to oral steroids. One of these patients however ceased their Phenergan within a few days and their implant was removed electively for a relatively mild inflammatory reaction.

Approximately 5 implants have been removed for signs of infection as well as the two that have been removed for an allergic inflammatory response. The risk of infection can be minimised and held below 1% with the use of prophylactic antibiotics such as flucloxacillin.

Selection of Patients and Special Warnings

The patients should be informed of the risks of removal for infection and allergic responses and should also be informed of the alternative of oral naltrexone. Implant naltrexone pellets should only be used on patients who are declaring clearly that they wish to cease their opiate dependence on a long-term basis.

The following checklist should be considered prior to inserting implants:

1) The patient should be able to sign a standard consent form to confirm they

understand that the product is available prior to open marketing on a Special Access basis to decrease the risk of premature death.

The patient should confirm that they understand that continuing research is occurring and that the product is unlicensed. It is the physician’s responsibility to ensure that the relevant consent documents are completed and signed prior to the procedure.

The patient should have no active infection in the skin close to where the implant is being inserted.

The patient should have no history of allergic reactions to local anaesthetics, naltrexone.

The patient should not be in liver failure.

The patient should be informed that removal of the implants may require admission to a private hospital theatre and that normally this is avoided in the first two weeks.

Special Precautions

Patients with a psychiatric history should have a carer sign their consent forms as well as them if this is practical.

CONTRA-INDICATIONS

Patients currently dependent on opioids not detoxed, acute hepatitis or liver failure.

Procedure for Implanting (patients free of opiates > 7 days)

For most patients no pre-medication is required. In order to decrease the risk of infection 2g of flucloxacillin and 2g of cephalexin is recommended pre-operatively. It is preferred to continue treatment with 1g of flucloxacillin 6 hourly for 72 hours.

The skin is prepared with appropriate antiseptic solutions (eg betadine solution) after selection of the site for the implant.

Selection of site:

The commonest site to be selected is the subcutaneous tissue between the anterior / superior iliac crest and the midline. The implant is usually placed just below the belt line or the bikini line.

Local anaesthetic:

Bupivicaine 0.5% with adrenaline (20ml) is usually diluted with the addition of 30ml of saline which is slowly injected into the subcutaneous tissue along a line approximately 12 – 14 cm long. With 50 ml of fluid injected and oval shaped raised area of skin provides the area where the implant is to be inserted.

Method of insertion:

A small incision 7 – 10mm long is made through the skin down to the subcutaneous tissues. Sterile forceps are then introduced into the subcutaneous tissue and a tunnel 15 – 20 mm long is created in the subcutaneous tissues by rotating the sterile forceps.

The bevel of the trocar containing naltrexone pellet is then inserted into the tunnel. By

rotating the syringe from side to side it is then possible to push the syringe along the subcutaneous tissues up to the flange of the trocar. The pellet is then inserted by pushing on the trocar plunger as the trocar is pulled back. The greater the distance between the pellet and the incision site the lower the risk of infection. For this reason, the trocar plunger should be pushed quite actively to make sure the pellets are at least 15 mm from the incision site.

Removal of suture:

It is normal practice to remove the suture on the 3^rd post-operative day.

Pain Relief Post-Operatively:

The use of non-steroidal treatment such as Celebrex 200mg daily for 5 days is recommended. In addition, paracetamol 4 hourly may be considered but is usually not necessary. The use of Bupivacaine provides pain relief for the first evening after treatment for most patients.

Procedure for Implanting (patients free of opiates < 7 days)

Patient should be encouraged to be opiate free for as long as they can cope with prior to the procedure of inserting naltrexone implants. For some patients this proves to be impossible and where the opiate free period is less than 4 days significant withdrawal reactions can be anticipated.

HYPERLINK “https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009” HOW SUPPLIED

Naltrexone implants are available in a box of 1 X 1.0 g Naltrexone pellet. Each pellet is individually blister packed in a trochar

Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). Naltrexone pellets should be implanted before their date of expiration to assure sterility requirements.

Supplied by:

Gluon Pharma Laboratories LLP

303, 3rd Floor, AC Market

Tardeo Road

Mumbai 400034, India

HYPERLINK “https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009” NALTREXONE IMPLANT PATIENT INFORMATION

What is Naltrexone Implant?

Naltrexone blocks the effects of narcotic medicines and alcohol.

Naltrexone implants are used to treat addiction to alcohol or narcotic drugs. It is also used to prevent narcotic addiction relapse.

Naltrexone Implants prevents the reward effects of opioids and alcohol with subsequent use.

Craving decrease substantially in those people on naltrexone, and that this craving reduction occurs very quickly, from the beginning of treatment (first 2-3 weeks) and doesn’t seem to return after that. There are certainly people who continue to have cravings, but this is a rather small proportion and usually occurs only after coming off medication. Those who maintain treatment with naltrexone have no cravings, and some believe that combining naltrexone with personal recovery work in a 12-step based program is especially effective.

Naltrexone implants may also be used for purposes not listed in this medication guide.

What are the possible side effects of naltrexone implant?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any of these serious side effects:

Blurred vision or eye problems

Fast heartbeat

Wheezing, difficulty breathing

Mood changes, hallucinations (seeing or hearing things), confusion, thoughts of hurting yourself

Nausea, stomach pain, low fever, loss of appetite, dark urine, clay-coloured stools, jaundice (yellowing of the skin or eyes)

Ear pain, ringing in your ears

Feeling light-headed, fainting

Skin rash or itching

Pain, redness, bruising, itching, swelling, oozing, skin changes, or a hard lump where the medication was implanted

Less serious side effects may include:

Feeling anxious, nervous, restless, or irritable

Increased thirst

Muscle or joint aches

Weakness or tiredness

Sleep problems (insomnia)

Decreased sex drive, impotence, or difficulty having an orgasm.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

What is the most important information I should know about naltrexone implants?

Do not use narcotic drugs or alcohol while you are being treated with naltrexone implants. Never try to overcome the effects of the medication by using large doses of narcotic drugs or alcohol. Doing so could result in dangerous effects, including coma and death. Ask your doctor before using any prescription or over-the-counter medicine to treat a cold, cough, diarrhoea, or pain during your treatment with naltrexone injection. These medicines may contain narcotics or alcohol.

Use of Naltrexone Implants does not eliminate or diminish substance abuse withdrawal symptoms.

Naltrexone implants may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

You may notice pain, redness, bruising, swelling, or a hard lump where the medication was implanted. Call your doctor if you have this type of reaction to the implant, especially if it does not clear up or gets worse within 2 weeks.

Wear a medical alert tag or carry an ID card stating that you use naltrexone implants. Any medical care provider who treats you should know that you are receiving this medication.

Alert your healthcare professional right away if you develop serious bouts of depression or suicidal thinking.

Families and caregivers of patients being treated with Naltrexone Implants should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s healthcare professional.

Additional forms of counselling and/or monitoring may be recommended during treatment with naltrexone implants.

You may be more sensitive to lower doses of opioids after Naltrexone Implant treatment is discontinued. Reduced tolerance is especially of concern at the end of a dosing interval, that is, near the end of the dosing cycle after the Naltrexone Implant was administered, or after a dose of Naltrexone Implant is missed. It is also important that you inform family members and the people closest to you of this increased sensitivity to opioids and the risk of overdose.

What should I discuss with my healthcare provider before receiving naltrexone implants?

Do not receive this implant if you are allergic to naltrexone, polyvinylpyrrolidone, stearic acid, ascorbic acid, triamcinolone or if you have:

A history of alcohol or narcotic drug use within the past 7-10 days; or

Drug or alcohol withdrawal symptoms.

To make sure you can safely use naltrexone implant, tell your doctor if you have any of these other conditions:

Kidney disease

Liver disease

A bleeding disorder such as haemophilia

FDA pregnancy category C. It is not known whether naltrexone implant will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether naltrexone implant passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How is the Naltrexone Implant Used?

Naltrexone implants are placed under the skin. The implants are usually given once every 3 months (every 10-12 weeks) and can be given only by a doctor in a clinic.

It is important to receive your naltrexone implants regularly to get the most benefit.

Avoid bathtubs and hot tubs, swimming or exercise for 7 days after implantation to minimize risk of the implant coming out.

Wear a medical alert tag or carry an ID card stating that you use naltrexone implants. Any medical care provider who treats you should know that you are receiving this medication.

Additional forms of counselling and/or monitoring may be recommended during treatment with naltrexone injection.

What happens if I miss a dose?

Call your doctor for instructions if you miss an appointment to receive your naltrexone implant.

What happens if I overdose?

Seek emergency medical attention

Overdose symptoms may include nausea, stomach pain, dizziness, or seizure (convulsions).

What should I avoid while using Naltrexone Implants?

Naltrexone may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Do not use narcotic drugs or alcohol while receiving naltrexone implants. Never try to overcome the effects of the medication by using large doses of narcotic drugs or alcohol. Doing so could result in dangerous effects, including coma and death. Ask your doctor before using any prescription or over-the-counter medicine to treat a cold, cough, diarrhoea, or pain while you are being treated with naltrexone implants. These medicines may contain narcotics or alcohol.

What other drugs will affect naltrexone implants?

The pain-relieving effects of any narcotic pain medications you use will be blocked if you use them during your treatment with naltrexone implants. Harmful side effects could also occur.

Tell your doctor about all other medicines you use, especially:

Buprenorphine

Butorphanol

Codeine

Hydrocodone

Hydromorphone

Levorphanol

Meperidine

Methadone

Morphine

Nalbuphine

Naloxone

Oxycodone

Oxymorphone

Propoxyphene

This list is not complete and other drugs may interact with naltrexone implants. Tell your doctor about all medications you use. This includes prescription, over the counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor can provide more information about naltrexone implants.