Buvidal

Patient Information Leaflet

Buvidal 8 mg prolonged-release injectable solution, 16 mg prolonged-release injectable solution, 24 mg prolonged-release injectable solution, 32 mg prolonged-release injectable solution, 64 mg prolonged-release injectable solution, 96 mg prolonged-release injectable solution, 128 mg prolonged-release injectable solution, 160 mg prolonged-release injectable solution

buprenorphine
Please read all of this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

What is in this leaflet

1. What Buvidal is and what it is used for
2. What you need to know before using Buvidal
3. How to use Buvidal
4. Possible side effects
5. How to store Buvidal
6. Contents of the pack and other information

1. What Buvidal is and what it is used for

Buvidal contains the active substance buprenorphine, which is a type of opioid medicine. It is used for the treatment of opioid dependence in patients who are also receiving medical, social, and psychological support.
Buvidal is indicated in adults and adolescents aged ≥16 years.

2. What you should know before taking Buvidal

Do not take Buvidal

• if you are allergic to buprenorphine or to any of the other ingredients of this medicine (listed in section 6).
• if you have severe respiratory problems
• if you have severe liver problems
• if you are intoxicated due to alcohol or suffer from tremors, sweating, anxiety, confusion, or hallucinations caused by alcohol

Warnings and precautions
Talk to your doctor before taking Buvidal if you have:

• asthma or other respiratory problems
• any liver disease such as hepatitis
• severe renal insufficiency
• certain heart rhythm conditions (long QT syndrome or prolonged QT interval)
• low blood pressure
• recently suffered head trauma or have a brain disorder
• a urinary disorder (especially related to prostate enlargement in men)
• thyroid problems
• an adrenal gland disorder (e.g. Addison's disease)
• gallbladder problems
• depression or other conditions treated with antidepressants. Using these medicines together with Buvidal may lead to serotonin syndrome, a potentially life-threatening condition (see “Other medicines and Buvidal”).
• if you have ever had an allergic reaction to latex.

Important points to be aware of

• Respiratory problems: Some people have died due to very slow or shallow breathing caused by taking buprenorphine together with other central nervous system depressants (substances that slow down certain brain activities) such as benzodiazepines, alcohol, or other opioids.
• Drowsiness: this medicine may cause drowsiness, especially when used with alcohol or other central nervous system depressants (substances that slow down certain brain activities) such as benzodiazepines, other medications that reduce anxiety or cause drowsiness, pregabalin, or gabapentin.
• Dependence: this medicine may cause dependence.
• Liver damage: liver damage may occur with buprenorphine, especially if misused. This could also occur in the presence of viral infections (chronic hepatitis C), alcohol abuse, anorexia (eating disorder), or use of other medicines that damage the liver. Your doctor may ask you to have regular blood tests to monitor your liver. Inform your doctor if you develop any liver problems before starting treatment with Buvidal.
• Withdrawal symptoms: this medicine may cause withdrawal symptoms if taken less than 6 hours after using a short-acting opioid (e.g., morphine, heroin) or less than 24 hours after using a long-acting opioid such as methadone.
• Blood pressure: this medicine may cause a sudden drop in blood pressure, leading to dizziness, if you stand up too quickly from a sitting or lying position.
• Diagnosis of unrelated medical conditions: this medicine may mask pain and make it difficult to diagnose certain illnesses. Do not forget to inform your doctor about your current treatment with this medicine.
• Sleep-related breathing disorders: Buvidal may cause sleep-related breathing disorders such as sleep apnea (pauses in breathing during sleep) and sleep-related hypoxemia (low blood oxygen levels during sleep). Symptoms may include breathing pauses during sleep, nighttime awakenings due to shortness of breath, difficulty maintaining sleep, or excessive daytime sleepiness. If you or someone else notices these symptoms, contact your doctor. Your doctor may consider reducing your dose.

Tolerance, dependence, and addiction
This medicine contains buprenorphine, which is an opioid medicine. Repeated use of opioids may
lead to reduced effectiveness of the medicine (you become accustomed to the medicine, known as
tolerance). Repeated use of buprenorphine may also lead to dependence, abuse, and addiction, with
a consequent risk of potentially fatal overdose.
Dependence or addiction may make you feel as if you are no longer able to control the amount of
medicine you take or how often you take it.
The risk of dependence or addiction varies from person to person. You may have a higher risk of
developing dependence or addiction to buprenorphine if:

• You or someone in your family has ever abused or been dependent on alcohol, prescription medicines, or illegal drugs (“addiction”).
• You are a smoker.
• You have ever had mood disorders (depression, anxiety, or personality disorders) or have been treated by a psychiatrist for other mental illnesses.

You may be showing signs of dependence or addiction if, while using buprenorphine, you notice any
of the following:

• You need to use the medicine for a longer period than recommended by your doctor
• You need to use a higher dose than recommended
• You are using the medicine for reasons other than prescribed, for example, to "stay calm" or "help sleep"
• You have made repeated unsuccessful attempts to stop or control use of the medicine
• You feel unwell when stopping the medicine and feel better once you restart it ("withdrawal effects")
  If you notice any of these signs, talk to your doctor to discuss the best treatment plan for you, including when and how to safely stop treatment (see section 3, If you stop taking Buvidal).

Children and adolescents
Buvidal must not be used in children under 16 years of age. You will be monitored more closely by your doctor if you are an adolescent (aged 16–17 years).

Other medicines and Buvidal
Tell your doctor if you are taking, have recently taken, or might take any other medicines.
Some medicines may increase the side effects of Buvidal and may cause very serious reactions.
It is particularly important that you inform your doctor if you are taking:

• benzodiazepines (used to treat anxiety or sleep disorders). Taking excessive amounts of a benzodiazepine together with Buvidal could be fatal, as both medicines can cause very slow and shallow breathing (respiratory depression). If you need a benzodiazepine, your doctor will prescribe the correct dose.
• gabapentinoids (gabapentin or pregabalin) (used to treat epilepsy or neuropathic pain). Taking excessive amounts of a gabapentinoid together with Buvidal could be fatal, as both medicines can cause very slow and shallow breathing (respiratory depression). You must use the dose prescribed by your doctor.
• alcohol or medicines containing alcohol. Alcohol may worsen the sedative effect of this medicine.
• other medicines that may make you drowsy, used to treat conditions such as anxiety, insomnia, seizures (epileptic fits), and pain. These medicines, when taken together with Buvidal, may slow down certain brain activities and reduce alertness and ability to drive or operate machinery. Examples of medicines that may cause drowsiness or reduce alertness include:
  • other opioids, such as methadone, certain painkillers, and cough medicines. These medicines may also increase the risk of opioid overdose
  • antidepressants (used to treat depression)
  • sedating antihistamines (used to treat allergic reactions)
  • barbiturates (used to induce sleep or sedation)
  • certain anxiolytics (used to treat anxiety disorders)
  • antipsychotics (used to treat psychiatric disorders such as schizophrenia)
  • clonidine (used to treat high blood pressure)
• opioid painkillers. These medicines may not work properly when taken with Buvidal and may increase the risk of overdose.
• naltrexone and nalmefene (used to treat addiction disorders), as they may prevent Buvidal from working properly. You must not take them at the same time as this medicine.
• some antiretrovirals (used to treat HIV infection) such as ritonavir, nelfinavir, or indinavir, as they may enhance the effects of this medicine.
• some antifungal medicines (used to treat fungal infections) such as ketoconazole and itraconazole, as they may enhance the effects of this medicine.
• macrolide antibiotics (used to treat bacterial infections) such as clarithromycin and erythromycin, as they may enhance the effects of Buvidal.
• some antiepileptic medicines (used to treat epilepsy), such as phenobarbital, carbamazepine, and phenytoin, as they may reduce the effect of Buvidal.
• rifampicin (used to treat tuberculosis). Rifampicin may reduce the effect of Buvidal.
• monoamine oxidase inhibitors (used to treat depression), such as phenelzine, isocarboxazid, iproniazid, and tranylcypromine, as they may enhance the effects of this medicine.
• antidepressants such as moclobemide, tranylcypromine, citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, venlafaxine, amitriptyline, doxepin, or trimipramine. These medicines may interact with Buvidal and may cause symptoms such as involuntary rhythmic muscle contractions, including muscles controlling eye movement, agitation, hallucinations, coma, excessive sweating, tremor, exaggerated reflexes, increased muscle contraction, and fever above 38°C. Contact your doctor if you experience any of these symptoms.
• medicines used to treat allergies, motion sickness, or nausea (antihistamines or antiemetics)
• muscle relaxants
• medicines used to treat Parkinson’s disease

Buvidal and alcohol
Do not consume alcoholic beverages while taking Buvidal (see section 2 Warnings and precautions).
Drinking alcohol with this medicine may increase drowsiness and the risk of breathing problems.

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before taking this medicine. The risks associated with the use of Buvidal in pregnant women are not known. Your doctor will help you decide whether you should continue taking the medicine during pregnancy.
Using this medicine during late pregnancy may cause withdrawal symptoms, including breathing problems, in the newborn. These may occur from several hours to several days after birth.
Check with your doctor before using Buvidal while breastfeeding, as this medicine is excreted in breast milk.

Driving and using machines
Buvidal may cause drowsiness and dizziness. These effects are more likely during treatment initiation and dose adjustments and may worsen if you drink alcohol or take other sedatives. Do not drive, operate tools or machinery, or perform hazardous activities until you know how this medicine affects you.

Buvidal contains alcohol
Buvidal 8 mg, 16 mg, 24 mg, and 32 mg contains 95.7 mg of alcohol (ethanol) per mL (10% w/w). The amount in one dose of this medicine is equivalent to less than 2 mL of beer or 1 mL of wine.
The small amount of alcohol in this medicine will not have noticeable effects.

3. How to use Buvidal

Buvidal must be administered exclusively by healthcare professionals.
Buvidal 8 mg, 16 mg, 24 mg, and 32 mg are administered once weekly. Buvidal 64 mg,
96 mg, 128 mg, and 160 mg are administered once monthly.
Your doctor will determine the best dose for you. During treatment, your doctor may adjust
the dose depending on how well the medicine is working.

Initial treatment
The first dose of Buvidal will be administered when you show clear signs of opioid withdrawal.
If you are dependent on short-acting opioids (e.g. morphine or heroin), the first dose of
Buvidal will be administered at least 6 hours after your last use of an opioid.
If you are dependent on long-acting opioids (e.g. methadone), your methadone dose
will be reduced to less than 30 mg per day before starting Buvidal. The first dose of
this medicine will be administered at least 24 hours after your last use of methadone.
If you are not already receiving sublingual buprenorphine (the same active substance present in Buvidal)
under the tongue, the recommended initial dose is 16 mg, with one or two additional doses of Buvidal 8 mg
administered at least 1 day apart from each other during the first week of
treatment. This results in a target dose of 24 mg or 32 mg during the first week of
treatment.
If you have never previously used buprenorphine, you will receive a 4 mg sublingual dose of buprenorphine and will be observed for one hour before receiving your first dose of Buvidal.
Buvidal may be used for monthly treatment, if appropriate for your case, once your weekly
Buvidal treatment has been stabilised.
If you are already taking sublingual buprenorphine, you may start receiving Buvidal the day after your last treatment. Your doctor will prescribe the appropriate initial dose of Buvidal for you based on the dose of sublingual buprenorphine you are currently taking.

Continuation of treatment and dose adjustment
During continued treatment with Buvidal, your doctor may reduce or increase your dose based on your needs. You may need to switch from weekly to monthly treatment or from monthly to weekly treatment. Your doctor will prescribe the correct dose for you.
During continued treatment, you may receive an additional dose of Buvidal 8 mg between your weekly or monthly treatments if your doctor considers it appropriate for your case.
The maximum weekly dose for patients receiving weekly treatment with Buvidal is 32 mg with an additional 8 mg dose. The maximum monthly dose for patients receiving monthly treatment with Buvidal is 160 mg.

Route of administration
Buvidal is administered via a single subcutaneous injection (under the skin) at any of the approved injection sites, such as the buttocks, thigh, abdomen, or upper arm.
You may receive multiple injections in the same injection area, but the exact injection sites will be different for each weekly or monthly injection, for a minimum period of 8 weeks.

If you take more buprenorphine than you should
If you have received more buprenorphine than prescribed, you must contact your doctor immediately, as this could cause very slow and shallow breathing, which could lead to death.
If you use too much buprenorphine, seek immediate medical help, as overdose may cause serious and potentially fatal breathing problems. Symptoms of overdose may include slower and weaker breathing, increased drowsiness, nausea, vomiting and/or difficulty speaking clearly or slurred speech. Your pupils may become smaller. Be aware of feeling faint, as this could be a sign of low blood pressure.

If you miss a dose of Buvidal
It is very important that you attend all your scheduled appointments for Buvidal administration. If you miss an appointment, contact your doctor to determine when to schedule your next dose.

If you stop treatment with Buvidal
Do not stop treatment without first consulting your doctor. Stopping treatment may cause withdrawal symptoms.
If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Immediately inform your doctor or seek urgent medical attention if you experience side effects such as:

• sudden wheezing, breathing difficulties, swelling of the eyelids, face, tongue, lips, throat or hands; skin rash or itching all over the body. These could be signs of a severe allergic reaction.
• if you start breathing more slowly or more weakly than usual (respiratory depression).
• if you start feeling faint, as this could be a sign of low blood pressure.

Also immediately inform your doctor if you experience side effects such as:

• severe tiredness, loss of appetite, or yellowing of the skin or eyes. These could be symptoms of liver damage.

Other side effects:
Very common side effects (may affect more than 1 in 10 people):

• insomnia (inability to sleep)
• headache
• nausea (feeling unwell)
• sweating, drug withdrawal syndrome, pain.

Common side effects (may affect up to 1 in 10 people):

• infection, influenza, sore throat and pain when swallowing, runny nose
• swollen glands (lymph nodes)
• hypersensitivity
• loss of appetite
• anxiety, restlessness, depression, hostility, nervousness, unusual thoughts, paranoia
• drowsiness, dizziness, migraine, burning or tingling sensation in hands and feet, fainting, tremor, increased muscle tension, speech disorders
• tearing, abnormal dilation or constriction of the pupil (the black part of the eye)
• palpitations
• low blood pressure
• cough, shortness of breath, yawning, asthma, bronchitis
• constipation, vomiting (nausea), stomach pain, flatulence (intestinal gas), indigestion, dry mouth, diarrhoea
• skin rash, itching, urticaria
• joint pain, back pain, muscle pain, muscle spasms, neck pain, bone pain
• pain during menstrual period
• reactions at the injection site, such as pain, itching, redness, swelling and hardening of the skin, swelling of the ankles, feet or fingers, weakness, feeling unwell, fever, chills, drug withdrawal syndrome in the newborn, chest pain
• abnormalities in liver function test results.

Uncommon side effects (may affect up to 1 in 100 people):

• skin infection at the injection site
• dizziness or spinning sensation (vertigo).

Not known (frequency cannot be estimated from the available data):

• hallucinations, feeling of happiness and excitement (euphoria)
• abnormal skin flushing
• painful or difficult urination
• reactions at the injection site, for example open sores, a swollen area with pus and death of cells or tissue at the injection site.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system referred to in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Buvidal

Buvidal must be administered only by healthcare professionals. Home use or self-administration by patients is not permitted.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton or syringe after Scad/EXP. The expiry date refers to the last day of that month.
Do not refrigerate or freeze.
Do not use this medicine if you notice visible particles or if it is cloudy.
Buvidal is for single use only. All used syringes must be discarded.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. These measures will help protect the environment.

6. Package contents and other information

What Buvidal contains

• The active substance is buprenorphine.
• The other ingredients are soybean phosphatidylcholine, glycerol dioleate, anhydrous ethanol (see section 2 "Buvidal contains alcohol") (only in the weekly formulation), and N-methylpyrrolidone (only in the monthly formulation).

The following syringes are available:
Weekly injection:
8 mg: pre-filled syringe containing 8 mg of buprenorphine in 0.16 mL of solution
16 mg: pre-filled syringe containing 16 mg of buprenorphine in 0.32 mL of solution
24 mg: pre-filled syringe containing 24 mg of buprenorphine in 0.48 mL of solution
32 mg: pre-filled syringe containing 32 mg of buprenorphine in 0.64 mL of solution
Monthly injection:
64 mg: pre-filled syringe containing 64 mg of buprenorphine in 0.18 mL of solution
96 mg: pre-filled syringe containing 96 mg of buprenorphine in 0.27 mL of solution
128 mg: pre-filled syringe containing 128 mg of buprenorphine in 0.36 mL of solution
160 mg: pre-filled syringe containing 160 mg of buprenorphine in 0.45 mL of solution

Description of the appearance of Buvidal and contents of the pack
Buvidal is a prolonged-release injectable solution. Each pre-filled syringe contains a pale yellow to yellow transparent liquid.

The following pack sizes are available:
Pre-filled syringes containing 8 mg, 16 mg, 24 mg, 32 mg, 64 mg, 96 mg, 128 mg and 160 mg of injectable solution.
Each pack contains 1 pre-filled syringe with cap, needle, needle cover, safety device, and 1 plunger rod.

Marketing Authorization Holder
Camurus AB
Ideon Science Park
SE-223 70 Lund
Sweden
[email protected]

Manufacturer
Rechon Life Science AB
Soldattorpsvägen 5
216 13 Limhamn
Sweden

More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

The following information is intended for healthcare professionals only:

Instructions for Use for Healthcare Personnel
Contents:
1. Important Information
2. Components of the Safety Syringe
3. Administration
4. Disposal of the Syringe

1. Important Information

• The injection must be administered ONLY into the subcutaneous tissue. Do not use if the safety syringe is broken or if the packaging is damaged.
• The needle cap of the safety syringe may contain rubber latex, which may cause allergic reactions in individuals sensitive to latex.
• Handle the safety syringe with care to avoid needlestick injuries. The safety syringe is equipped with a needle protection safety device that activates at the end of the injection. The needle cap will help prevent needlestick injuries.
• Do not remove the needle cap from the safety syringe until ready to administer the injection. Once the needle cap has been removed, never attempt to re-cap the needle.
• Dispose of the used safety syringe immediately after use. Do not reuse the safety syringe.

2. Components of the safety syringe

Figure 1: Safety syringe: Before use Safety syringe: After use
a) Needle shield (With needle protection mechanism
b) Protective syringe body activated)
c) Protective syringe rings
d) Plunger
e) Plunger tip
Note that the minimum injection volume is barely visible in the viewing window as the projection of the safety device "covers" part of the glass barrel near the needle.

• Do not touch the protective syringe body until ready for injection. Handling it may cause the protective syringe body to activate prematurely.
• Do not use the product if it has fallen onto a hard surface or has been damaged. Use a new product for injection.

3. Administration

• Remove the syringe from the cardboard box: take the syringe by holding the protective barrel.
• Holding the syringe firmly near the inspection window, insert the plunger rod into the designated cap by gently rotating the plunger rod clockwise until it locks into place (see Figure 2).

Figure 2 Before After

• Carefully inspect the safety syringe:
  • Do not use the safety syringe after the expiration date stated on the cardboard box or syringe label.
  • A small air bubble may be present, which is normal.
  • The liquid should be clear and transparent. Do not use the safety syringe if the liquid contains particles or appears cloudy.
• Choose the injection site. Injections should be alternated between the gluteal region, thigh, abdomen, or upper arm (see Figure 3), allowing a minimum of 8 weeks before re-injecting at a previously used site. Avoid injecting around the waistline or within 5 cm of the navel.

Figure 3

• Put on gloves and disinfect the injection site using a circular motion with an alcohol wipe (not provided in the package). Do not touch the disinfected area again before injection.
• Holding the safety syringe by the protective barrel as shown (see Figure 4), gently remove the needle cap. Immediately dispose of the needle cap (never attempt to reattach it to the needle). A drop of liquid may appear at the tip of the needle. This is normal.

Figure 4

• Lift the skin at the injection site by pinching it between the thumb and a finger as illustrated (see Figure 5).
• Hold the safety syringe as shown and insert the needle at an angle of approximately 90° (see Figure 5). Push the needle fully in.

Figure 5

• Holding the syringe as illustrated (see Figure 6), slowly press the plunger until the plunger head locks between the protective rings of the syringe and the entire solution has been injected.

Figure 6

• Gently withdraw the needle from the skin. It is recommended to keep the plunger fully depressed while carefully lifting the syringe away from the injection site (see Figure 7).

Figure 7

• As soon as the needle is completely withdrawn from the skin, slowly remove your thumb from the plunger and allow the protective shield of the syringe to automatically cover the exposed needle (see Figure 8). There may be minor bleeding at the injection site; if necessary, wipe gently with a cotton ball or gauze.

Figure 8

4. Disposal of the syringe

Unused medicine and waste materials derived from this medicine must be disposed of in accordance with
local applicable regulations.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND REASONS FOR THE VARIATION OF THE TERMS OF THE
MARKETING AUTHORISATION(S)
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Reports (PSURs) for buprenorphine (all formulations except implants), the PRAC's scientific conclusions are as follows:
In view of the available data from spontaneous reports and the literature on interactions between opioids and gabapentinoids and anticholinergics, and considering the existing warnings in the product information of other opioid-containing products, the PRAC concluded that the product information for buprenorphine-containing products (all formulations except implants) should be amended accordingly.
In view of the available literature data and spontaneous reports on the risk of paediatric poisoning, including some fatal cases, the PRAC concluded that the package leaflet for buprenorphine-containing products (all formulations except implants) should be amended accordingly (except for those products for which home use by patients is not permitted according to the product information instructions).
In view of the available data on the risk of medication errors related to incorrect routes of administration (e.g. intradermal, intramuscular, intravenous), the PRAC concluded that the product information for buprenorphine-containing products (all formulations except implants) intended only for subcutaneous injection should be amended accordingly.
In view of the available data on the risk of substance dependence/abuse of narcotic drugs from post-marketing case reports and literature data, and considering the existing warnings in the product information of other opioid-containing products, the PRAC concluded that the product information for buprenorphine-containing products (all formulations except implants) should be updated to strengthen the labelling regarding the risk of substance dependence/abuse of narcotic drugs, by adding the negative consequences of opioid use disorder and the identified risk factors, in line with the wording already applied for other opioids.
In view of the available data on dental caries from the literature and spontaneous reports, including cases with a close temporal relationship, and in view of a plausible mechanism of action, the PRAC considers that a causal relationship between oromucosal buprenorphine (all formulations except implants) and dental caries is at least a plausible hypothesis. The PRAC concluded that the product information for oromucosal buprenorphine-containing products (all formulations except implants) should be amended accordingly.
Having reviewed the PRAC's recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the respective general conclusions and the rationale of the recommendation.
Reasons for the variation of the terms of the marketing authorisations
Based on the scientific conclusions on buprenorphine (all formulations except implants), the CHMP considers that the benefit-risk balance of buprenorphine-containing medicinal products (all formulations except implants) remains favourable, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).