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PALLADONE, günlük, 24 saat uzun süreli opioid tedavisi gerektirecek kadar şiddetli ve alternatif tedavi seçeneklerinin yetersiz olduğu opioide toleranslı hastalarda ağrının yönetimi için endikedir.

Opioid toleranslı olarak kabul edilen hastalar, bir hafta veya daha uzun süre günde en az 60 mg oral morfin, 25 mcg transdermal fentanil / saat, 30 mg oral oksikodon / gün, 8 mg oral hidromorfon / gün, 25 mg oral oksimorfon alan hastalardır. / gün veya başka bir opioidin ekziyaljezik dozu.

Kullanım Sınırlamaları

• Opioidlerle bağımlılık, kötüye kullanım ve kötüye kullanım riskleri nedeniyle, önerilen dozlarda bile ve uzun süreli salınımlı opioid formülasyonlarla aşırı doz ve ölüm riskleri nedeniyle, alternatif tedavi seçenekleri olan hastalarda (örn.opioid olmayan analjezikler veya derhal salınan opioidler) etkisizdir, tolere edilmez veya ağrının yeterli yönetimini sağlamak için yetersizdir.
• PALLADONE gerektiğinde (prn) analjezik olarak gösterilmez.

İlk Dozlama

PALLADONE sadece kronik ağrının yönetimi için güçlü opioidlerin kullanımı konusunda bilgili sağlık uzmanları tarafından reçete edilmelidir.

Solunum depresyonu riski nedeniyle, PALLADONE sadece opioid toleranslı hastalarda kullanım için endikedir. PALLADONE tedavisine başlarken diğer tüm uzun süreli salınan opioidleri durdurun veya inceltin. PALLADONE sadece opioide toleranslı hastalarda kullanım için olduğundan, ilk opioid olarak PALLADONE'da herhangi bir hastaya başlamayın.

Opioide toleranslı olarak kabul edilen hastalar, günde en az 60 mg morfin veya günde en az 30 mg oral oksikodon veya günde en az 8 mg oral hidromorfon veya bir hafta veya daha uzun süre başka bir opioidin ekziyaljezik dozu alan hastalardır.

Her hasta için doz rejimini ayrı ayrı başlatın; hastanın önceki analjezik tedavi deneyimini ve bağımlılık, istismar ve yanlış kullanım için risk faktörlerini dikkate alarak. Özellikle PALLADONE ile tedaviye başlamanın ilk 24 ila 72 saati içinde solunum depresyonu için hastaları yakından izleyin

PALLADONE uzatılmış salimli kapsüller bütün olarak alınmalıdır. PALLADONE kapsüllerinin ezilmesi, çiğnemesi veya çözülmesi, kontrolsüz hidromorfon verilmesine neden olur ve aşırı doz veya ölüme yol açabilir.

Diğer Oral Opioidlerden PALLADONE'a dönüşüm

PALLADONE tedavisi başlatıldığında 24 saat boyunca tüm diğer opioid ilaçlarını durdurun.

Opioid eşdeğerlerinin yararlı tabloları kolayca mevcut olsa da, farklı opioid ilaçların ve ürünlerin göreceli gücünde önemli ölçüde hastalar arası değişkenlik vardır. Bu nedenle, bir hastanın 24 saatlik oral hidromorfon gereksinimlerini hafife almak ve kurtarma ilacı sağlamak tercih edilir (ör., derhal serbest bırakılan opioid), advers reaksiyona neden olabilecek 24 saatlik oral hidromorfon gereksinimlerini abartmaktan daha fazladır.

Açık etiketli titrasyon periyodu olan bir PALLADONE klinik çalışmasında, hastalar ilk PALLADONE dozu için bir kılavuz olarak Tablo 1 kullanılarak önceki opioidlerinden PALLADONE'a dönüştürüldü. Önerilen başlangıç PALLADONE dozu, günlük hidromorfon gereksiniminin hesaplanan tahmininin% 50'sidir. Tablo 1'i kullanarak tahmini günlük hidromorfon gereksinimini hesaplayın.

Tablo 1'deki bilgileri kullanırken aşağıdakileri göz önünde bulundurun:

• Bu değil ekzik dozların bir tablosu.
• Bu tablodaki dönüşüm faktörleri yalnızca dönüşüm içindir dan listelenen oral opioid analjeziklerden biri to PALLADONE .
• Tablo yapamaz dönüştürmek için kullanılabilir dan PALLADONE başka bir opioide. Bunu yapmak, yeni opioid dozunun fazla tahmin edilmesine neden olur ve ölümcül aşırı doza neden olabilir.

Tablo 1: PALLADONE * 'a Dönüşüm Faktörleri

Tablo 1'i kullanarak tahmini PALLADONE dozunu hesaplamak için:

• Tek bir opioid kullanan hastalar için, opioidin mevcut toplam günlük dozunu toplayın ve ardından yaklaşık oral hidromorfon günlük dozunu hesaplamak için toplam günlük dozu dönüşüm faktörü ile çarpın.
• Birden fazla opioid rejimindeki hastalar için, her opioid için yaklaşık oral hidromorfon dozunu hesaplayın ve günlük toplam hidromorfon dozunu elde etmek için toplamları toplayın.
• Sabit oranlı opioid / opioid olmayan analjezik ürünler rejimindeki hastalar için, dönüşümde bu ürünlerin sadece opioid bileşenini kullanın.

Dozu her zaman gerekirse mevcut uygun PALLADONE mukavemetine / güçlerine yuvarlayın.

Tek bir opioidden PALLADONE'a dönüşüm örneği:

Adım 1: Opioidin toplam günlük dozunu toplayın

• 30 mg oksikodon 2 kez = toplam günlük 60 mg oksikodon dozu

Adım 2: Tablo 1'i kullanarak mevcut opioidin toplam günlük dozuna dayanarak oral hidromorfonun yaklaşık eşdeğer dozunu hesaplayın

• Günlük 60 mg oksikodon x Dönüşüm Faktörü günlük 0.25 = 15 mg oral hidromorfon

Adım 3: Hesaplanan oral hidromorfon dozunun% 50'si olan her 24 saatte bir verilecek yaklaşık başlangıç PALLADONE dozunu hesaplayın. Gerekirse, mevcut uygun PALLADONE kapsül kuvvetlerine yuvarlayın.

• 15 mg'ın% 50'si günde bir kez 6 mg PALLADONE başlangıç dozudur
• Her hasta için ayrı ayrı ayarlayın

Ağrı yönetimi yeni opioid üzerinde stabil olana kadar yakın gözlem ve sık titrasyon gereklidir. Hastaları opioid yoksunluğu belirtileri ve semptomları veya hastaları PALLADONE'a dönüştürdükten sonra aşırı sedasyon / toksisite belirtileri açısından izleyin

Transdermal Fentanil'den PALLADONE'a dönüşüm

Transdermal fentanil yamasının çıkarılmasından on sekiz saat sonra PALLADONE tedavisi başlatılabilir. 24 saatlik PALLADONE dozunu hesaplamak için 25 mcg / saat fentanil transdermal yamayı 12 mg PALLADONE'a dönüştürün. Daha sonra PALLADONE dozunu% 50 azaltın.

Örneğin:

Adım 1: Transdermal fentanil dozunu belirleyin.

• 75 mg transdermal fentanil

Adım 2: 25 mg / saat fentanil transdermal yamanın 12 mg PALLADONE dönüşüm faktörünü kullanın

• 75 mg transdermal fentanil: günlük 36 mg PALLADONE dozu

Adım 3: Dönüştürülen dozun% 50'si olan her 24 saatte bir verilecek yaklaşık başlangıç PALLADONE dozunu hesaplayın. Gerekirse, mevcut uygun PALLADONE tablet kuvvetlerine yuvarlayın.

• 36 mg'ın% 50'si, günde bir kez 16 mg PALLADONE'a yuvarlanacak olan 18 mg'lık bir başlangıç dozu ile sonuçlanır
• Her hasta için ayrı ayrı ayarlayın

Metadon'dan PALLADONE'a dönüşüm

Metadondan diğer opioid agonistlerine dönüşürken yakından izleme özellikle önemlidir. Metadon ve diğer opioid agonistleri arasındaki oran, önceki doza maruz kalmanın bir fonksiyonu olarak büyük ölçüde değişebilir. Metadon uzun bir yarı ömre sahiptir ve plazmada birikebilir.

Terapinin Titrasyonu ve Bakımı

PALLADONE'u yeterli analjezi sağlayan ve advers reaksiyonları en aza indiren bir doza ayrı ayrı titre edin. Ağrı kontrolünün sürdürülmesini ve advers reaksiyonların göreceli insidansını ve ayrıca bağımlılık, kötüye kullanım veya yanlış kullanımın gelişimini izlemek için PALLADONE alan hastaları sürekli olarak yeniden değerlendirin. İlk titrasyon dahil analjezik gereksinimlerin değiştiği dönemlerde reçete yazan, sağlık ekibinin diğer üyeleri, hasta ve bakıcı / aile arasında sık iletişim önemlidir. Kronik tedavi sırasında, opioid analjeziklere olan sürekli ihtiyacı periyodik olarak yeniden değerlendirin.

PALLADONE'un plazma seviyeleri 18 ila 24 saat boyunca korunur. PALLADONE dozaj ayarlamaları, yeterli analjezi elde etmek için gerektiğinde her 3 ila 4 günde bir 4 ila 8 mg'lık artışlarla yapılabilir.

Atılım ağrısı yaşayan hastalar PALLADONE dozunda bir artış gerektirebilir veya uygun bir dozda derhal salınan analjezik ile kurtarma ilacına ihtiyaç duyabilir. Doz stabilizasyonundan sonra ağrı seviyesi artarsa, PALLADONE dozunu artırmadan önce artan ağrı kaynağını belirlemeye çalışın.

Kabul edilemez opioid ile ilişkili advers reaksiyonlar gözlenirse, sonraki dozlar azaltılabilir. Ağrı yönetimi ile opioid ile ilişkili advers reaksiyonlar arasında uygun bir denge elde etmek için dozu ayarlayın.

PALLADONE'un durdurulması

Bir hasta artık PALLADONE ile tedaviye ihtiyaç duymadığında, opioide toleranslı hastada yoksunluk belirtilerini ve semptomlarını önlemek için, tedavinin kesilmesinden önce her 2 veya 3 günde bir% 25 ila% 50 oranında dozları yavaş yavaş azaltın. .

Kullanılmayan PALLADONE'u atmak için kalan tüm kapsülleri tuvalete yıkayın veya sertifikalı bir ilaç geri alma programında yetkililere havale edin.

Karaciğer yetmezliği

Normal karaciğer fonksiyonuna sahip hastalar için reçete edilecek PALLADONE dozunun% 25'inde orta şiddette karaciğer yetmezliği olan hastalara başlayın. PALLADONE ile tedaviye başlanırken ve doz titrasyonu sırasında solunum ve merkezi sinir sistemi depresyonu için orta şiddette karaciğer yetmezliği olan hastaları yakından izleyin. Şiddetli karaciğer yetmezliği olan hastalar için alternatif analjeziklerin kullanılması önerilir.

Böbrek Bozukluğu

Normal böbrek fonksiyonu olan hastalar için reçete edilecek PALLADONE dozunun% 25'inde orta derecede böbrek yetmezliği olan hastalara ve% 25'inde şiddetli böbrek yetmezliği olan hastalara başlayın. PALLADONE ile tedaviye başlanırken ve doz titrasyonu sırasında solunum ve merkezi sinir sistemi depresyonu için böbrek yetmezliği olan hastaları yakından izleyin. PALLADONE günde sadece bir kez uygulama için tasarlandığından, ciddi böbrek yetmezliği olan hastalarda dozlama aralığı ile daha fazla esnekliğe izin verebilecek alternatif bir analjezik kullanmayı düşünün.

PALLADONE Yönetimi

Hastalara PALLADONE kapsüllerini sağlam yutmasını söyleyin. Potansiyel olarak ölümcül bir hidromorfon dozunun hızlı bir şekilde salınması ve emilmesi riski nedeniyle kapsüller ezilmemeli, çözülmemeli veya çiğnenmemelidir.

PALLADONE kontrendikedir:

• Opioid toleranssız hastalar. Opioid toleranslı olmayan hastalarda ölümcül solunum depresyonu oluşabilir.
• Önemli solunum depresyonu olan hastalar
• İzlenmeyen bir ortamda veya resüsitatif ekipman yokluğunda akut veya şiddetli bronşiyal astımı olan hastalar
• Bilinen veya şüphelenilen felç ileuslu hastalar
• Gastrointestinal sistemin daralmasına neden olan cerrahi prosedürleri ve / veya altta yatan hastalığı olan veya gastrointestinal sistemin veya gastrointestinal tıkanıklığın “kör döngüleri” olan hastalar.
• Aşırı duyarlılığı olan hastalar (ör., anafilaksi) hidromorfon veya sülfit içeren ilaçlara.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Addiction, Abuse, And Misuse

PALLADONE contains hydromorphone, a Schedule II controlled substance. As an opioid, PALLADONE exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as PALLADONE deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydromorphone present.

Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed PALLADONE and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused.

Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing PALLADONE, and monitor all patients receiving PALLADONE for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of PALLADONE for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as PALLADONE, but use in such patients necessitates intensive counseling about the risks and proper use of PALLADONE along with intensive monitoring for signs of addiction, abuse, and misuse.

Abuse or misuse of PALLADONE by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of hydromorphone and can result in overdose and death.

Opioid agonists such as PALLADONE are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing PALLADONE. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

Life-threatening Respiratory Depression

Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient's clinical status. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.

While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of PALLADONE, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with PALLADONE and following dose increases.

To reduce the risk of respiratory depression, proper dosing and titration of PALLADONE are essential. Overestimating the PALLADONE dose when converting patients from another opioid product can result in fatal overdose with the first dose.

Accidental ingestion of even one dose of PALLADONE, especially by children, can result in respiratory depression and death due to an overdose of hydromorphone.

Neonatal Opioid Withdrawal Syndrome

Prolonged use of PALLADONE during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.

Interactions With Central Nervous System Depressants

Hypotension, profound sedation, coma, respiratory depression, and death may result if PALLADONE is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).

When considering the use of PALLADONE in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient's response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient's use of alcohol or illicit drugs that cause CNS depression. If the decision to begin PALLADONE is made, start with 1/3 to ½ the calculated starting dose of PALLADONE, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use In Ederly, Cachectic, and Debilitated Patients

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating PALLADONE and when PALLADONE is given concomitantly with other drugs that depress respiration.

Use In Patients With Chronic Pulmonary Disease

Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy and titrating with PALLADONE, as in these patients, even usual therapeutic doses of PALLADONE may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.

Hypotensive Effect

PALLADONE may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g. phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of PALLADONE.

Use In Patients With Head Injury Or Increased Intracranial Pressure

Monitor patients taking PALLADONE who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with PALLADONE. PALLADONE may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of PALLADONE in patients with impaired consciousness or coma.

Use In Patients with Gastrointestinal Conditions

PALLADONE is contraindicated in patients with paralytic ileus. Avoid the use of PALLADONE in patients with other GI obstruction.

Because the PALLADONE capsule is nondeformable and does not appreciably change in shape in the GI tract, PALLADONE is contraindicated in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel's diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

It is possible that PALLADONE capsules may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

The hydromorphone in PALLADONE may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Sulfites

PALLADONE contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

Use In Patients With Convulsive Or Seizure Disorders

The hydromorphone in PALLADONE may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during PALLADONE therapy.

Avoidance Of Withdrawal

Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbuphine, and butorphanol) or partial agonists (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including PALLADONE. In these patients, mixed agonists/antagonist and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.

When discontinuing PALLADONE, gradually taper the dose. Do not abruptly discontinue PALLADONE.

Driving And Operating Machinery

PALLADONE may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of PALLADONE and know how they will react to the medication.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Addiction, Abuse, and Misuse

Inform patients that the use of PALLADONE, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose or death. Instruct patients not to share PALLADONE with others and to take steps to protect PALLADONE from theft or misuse.

Life-threatening Respiratory Depression

Inform patients of the risk of life-threatening of respiratory depression, including information that the risk is greatest when starting PALLADONE or when the dose is increased, and that it can occur even at recommended doses. Advise patients how to recognize respiratory depression and to seek medical attention if breathing difficulties develop.

Accidental Ingestion

Inform patients that accidental ingestion, especially in children, may result in respiratory depression or death. Instruct patients to take steps to store PALLADONE securely and to dispose of unused PALLADONE by flushing the capsules down the toilet.

Neonatal Opioid Withdrawal Syndrome

Inform female patients of reproductive potential that prolonged use of PALLADONE during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated.

Interactions with Alcohol and other CNS Depressants

Inform patients that potentially serious additive effects may occur if PALLADONE is used with alcohol or other CNS depressants, and not to use such drugs unless supervised by a health care provider.

Important Administration Instructions

Instruct patients how to properly take PALLADONE, including the following:

• Swallowing PALLADONE whole
• Not crushing, chewing, splitting or dissolving the capsule
• Using PALLADONE exactly as prescribed to reduce the risk of life-threatening adverse reactions (e.g., respiratory depression)
• Not discontinuing PALLADONE without first discussing the need for a tapering regimen with the prescriber

Gastrointestinal Blockage

Advise patients that people with certain stomach or intestinal problems such as narrowing of the intestines or previous surgery may be at higher risk of developing a blockage. Symptoms include abdominal distension, abdominal pain, severe constipation, or vomiting. Instruct patients to contact their healthcare provider immediately if they develop these symptoms.

Hypotension

Inform patients that PALLADONE may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position).

Driving or Operating Heavy Machinery

Inform patients that PALLADONE may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication.

Constipation

Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention.

Anaphylaxis

Inform patients that anaphylaxis has been reported with ingredients contained in PALLADONE. Advise patients how to recognize such a reaction and when to seek medical attention.

Pregnancy

Advise female patients that PALLADONE can cause fetal harm and to inform the prescriber if they are pregnant or plan to become pregnant.

Disposal

Advise patients to flush the unused capsules down the toilet when PALLADONE is no longer needed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted in animals.

Hydromorphone was negative in the in vitro bacterial reverse mutation assay and in the in vivo mouse micronucleus assay. Hydromorphone was negative in the mouse lymphoma assay in the absence of metabolic activation, but was positive in the mouse lymphoma assay in the presence of metabolic activation. Morphinone, an impurity, tested as a besylate salt was negative in the in vitro bacterial reverse mutation assay and negative in the in vivo mouse micronucleus assay. Morphinone was positive in the Chinese Hamster Ovary Cell Chromosomal Aberration test in the absence and presence of metabolic activation.

Hydromorphone did not affect fertility in rats at oral doses up to 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.

Mutagenesis

Hydromorphone was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay). Hydromorphone was not clastogenic in either the in vitro human lymphocyte chromosome aberration assay or the in vivo mouse micronucleus assay.

Impairment of Fertility

Hydromorphone given orally to rats during the mating period caused a slight but statistically significant reduction in implantations at 6.25 mg/kg/day (~1.2 times the human exposure following to 32 mg/day).

Use In Specific Populations

Pregnancy

Clinical Considerations

Fetal/neonatal adverse reactions

Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.

Teratogenic Effects -Pregnancy Category C

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

Hydromorphone was not teratogenic in female rats given oral doses up to 10 mg/kg or female rabbits given oral doses up to 50 mg/kg during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 3-fold and 6-fold higher than a 32 mg human daily oral dose based on exposure (AUC0-24h).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 278 mg/kg during organogenesis (gestation days 8 to10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately 3-fold higher and < 1-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effect

In a rat pre-and post-natal study, an increase in pup mortality and a decrease in pup body weight which was associated with maternal toxicity was observed at doses of 2 and 5 mg/kg/day. The maternal no effect level for hydromorphone was 0.5 mg/kg/day which is < 1-fold lower than a 32 mg human daily oral dose on a body surface area. Hydromorphone had no effect on pup development or reproduction when given to female rats during the pre-natal and postnatal periods up to a dose of 5 mg/kg which is equivalent to a 32 mg human daily oral dose on a body surface area basis.

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal. Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor And Delivery

PALLADONE is not for use in women during and immediately prior to labor, where shorter acting analgesics or other analgesic techniques are more appropriate. Occasionally, opioid analgesics may prolong labor by temporarily reducing the strength, duration, and frequency of uterine contractions. However, these effects are not consistent and may be offset by an increased rate of cervical dilatation which tends to shorten labor.

Opioids cross the placenta and may produce respiratory depression and psychophysiologic effects in neonates. Closely observe neonates whose mothers received opioid analgesics during labor for signs of respiratory depression. An opioid antagonist, such as naloxone, should be available for reversal of opioid-induced respiratory depression in the neonate in such situations.

Nursing Mothers

Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving PALLADONE since hydromorphone is excreted in the milk.

Pediatric Use

The safety and effectiveness of PALLADONE in pediatric patients below the age of 18 have not been established.

Geriatric Use

Hepatic Impairment

PALLADONE was not studied in patients with severe hepatic impairment and are not recommended for use in such patients. Care in initial dose selection and careful observation are recommended in patients with evidence of mild to moderate hepatic impairment.

Renal Impairment

In patients with mild to moderate renal impairment, based on calculated creatinine clearance, the concentrations of hydromorphone in plasma were slightly higher than in subjects with normal renal function.

Hydromorphone may impair the ability to drive and use machines. This is particularly likely at the initiation of treatment with hydromorphone, after dose increase or product rotation and if hydromorphone is combined with alcohol or other CNS depressant substances. Patients stabilised on a specific dosage will not necessarily be restricted. Patients should therefore consult with their physician whether driving or the use of machinery is permitted.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

- The medicine is likely to affect your ability to drive.

- Do not drive until you know how the medicine affects you.

- It is an offence to drive while you have this medicine in your body over a specified limit unless you have a defence (called the 'statutory defence'). This defence applies when:

o The medicine has been prescribed to treat a medical or dental problem; and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine.

- Please note that it is still an offence to drive if you are unfit because of the medicine (i.e. your ability to drive is being affected).

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/drug-driving-law

Aşağıdaki ciddi advers reaksiyonlar etiketlemenin başka bir yerinde tartışılmaktadır:

• Bağımlılık, Kötüye Kullanım ve Kötüye Kullanım
• Hayatı Tehdit Eden Solunum Depresyonu
• Yenidoğan Opioid Yoksunluk Sendromu
• Diğer CNS Depresanları ile Etkileşimler
• Hipotansif Etki
• Gastrointestinal Etkiler
• Nöbetler

Klinik Araştırma Deneyimi

PALLADONE'un güvenliği, orta ila şiddetli ağrısı olan 612 hastayı içeren çift kör klinik çalışmalarda değerlendirildi. Kontrollü çalışmalardan daha yüksek dozlarda daha uzun süre kullanıldığında PALLADONE'un güvenliğini değerlendirmek için 143 kanser ağrısı olan hastayı içeren açık etiketli bir uzatma çalışması yapılmıştır. Hastalar birkaç ay boyunca (1 ila ≥ 52 hafta arasında) günde ortalama 40 ila 50 mg PALLADONE (12 ila 500 mg / gün arasında) dozlarıyla tedavi edildi.

Klinik kullanımda PALLADONE tedavisi ile ilişkili olabilecek ciddi advers reaksiyonlar, solunum depresyonu, apne, solunum durması ve daha az derecede dolaşım depresyonu, hipotansiyon, şok veya kalp durması gibi diğer opioid analjeziklerinkine benzer.

Kontrollü Denemelerde Bildirilen Olumsuz Olaylar

Tablo 2, plasebo kontrollü çalışmalarda hastaların en az% 2'sinde bildirilen ve PALLADONE 12 mg kapsül ile tedavi edilenler için plasebo ile tedavi edilenlerden daha yüksek olan tedavi ortaya çıkan belirti ve semptomları listelemektedir.

Tablo 2: Malign Olmayan Ağrı için PALLADONE Kapsülleri Alan Hastalarda İnsidans ile Plasebo Kontrollü Klinik Çalışmalarda Bildirilen Olumsuz Olaylar

Klinik Araştırmalarda Gözlenen Olumsuz Olaylar

PALLADONE, tamamlanmış klinik çalışmalar sırasında 785 kişiye uygulanmıştır. PALLADONE'a maruz kalma koşulları ve süresi büyük ölçüde değişmiştir ve açık etiketli ve çift kör çalışmalar, kontrolsüz ve kontrollü çalışmalar, yatarak ve ayaktan çalışmalar, sabit doz ve titrasyon çalışmalarını içermektedir. Bu maruziyetle ilişkili istenmeyen olaylar, kendi seçtikleri terminoloji kullanılarak klinik araştırmacılar tarafından kaydedilmiştir.

Bu kategoriler aşağıdaki listede kullanılmaktadır. Frekanslar, PALLADONE alırken bu olayı yaşayan 785 hastanın oranını temsil etmektedir. Bu tabloya dahil edilen tüm advers olaylar en az bir hastada meydana geldi. Olaylar vücut sistemine göre sınıflandırılır ve aşağıdaki tanımlar kullanılarak listelenir: sık görülen advers olaylar - en az 1/100 hastada meydana gelenler; insidansı% 1'den az olan advers olaylar seyrek kabul edilir. Bu advers olaylar mutlaka PALLADONE tedavisi ile ilişkili değildir ve çoğu durumda kontrollü çalışmalarda plasebo ile tedavi edilen hastalarda benzer sıklıkta gözlenmiştir.

Sık Yan Etkiler

Bir bütün olarak vücut: baş ağrısı, asteni, ağrı, karın ağrısı, ateş, göğüs ağrısı, enfeksiyon, titreme, halsizlik, boyun ağrısı, karsinom, kazara yaralanma

Kardiyovasküler Sistem: vazodilatasyon, taşikardi, migren

Sindirim Sistemi: bulantı, kabızlık, kusma, ishal, hazımsızlık, iştahsızlık, ağız kuruluğu, bulantı ve kusma, disfaji, şişkinlik

Hemik ve Lenfatik Sistem: anemi, lökopeni

Metabolik ve Beslenme Bozuklukları : periferik ödem, dehidrasyon, ödem, genel ödem, hipokalemi, kilo kaybı

Kas-iskelet sistemi: artralji, kemik ağrısı, bacak krampları, kas ağrısı

Sinir Sistemi: uyku hali, baş dönmesi, sinirlilik, karışıklık, uykusuzluk, anksiyete, depresyon, hipertoni, hipestezi, parestezi, titreme, anormal düşünme, halüsinasyonlar, konuşma bozukluğu, ajitasyon, amnezi, kulak çınlaması, anormal yürüyüş

Solunum Sistemi: dispne, öksürük arttı, rinit, farenjit, pnömoni, burun kanaması, hıçkırık, hipoksi, plevral efüzyon

Cilt ve Ekler : kaşıntı, terleme, döküntü

Özel Duyular: ambliyopi, tat sapması

Ürogenital Sistem: dizüri, idrar kaçırma

Nadir Olumsuz Olaylar

Bir bütün olarak vücut: yüz ödemi, asit, alerjik reaksiyon, selülit, aşırı doz, hipotermi, neoplazma, ışığa duyarlılık reaksiyonu, sepsis, yan ağrı

Kardiyovasküler Sistem: hipertansiyon, hipotansiyon, senkop, derin tromboflebit, aritmi, postüral hipotansiyon, atriyal fibrilasyon, solgunluk, bradikardi, elektrokardiyogram anormal, miyokard enfarktüsü, çarpıntı, anjina pektoris, konjestif kalp yetmezliği, QT aralığı uzamış, supraventriküler taşikardi, tromboz, hemorrorror,

Sindirim Sistemi: dışkı impaksiyonu, bağırsak tıkanıklığı, anormal dışkı, dışkı inkontinansı, karaciğer yetmezliği, iştah artışı, kolanjit, kolesistit, kolit, enterokolit, hepatomegali, sarılık, karaciğer fonksiyon testleri anormal, biliyer spazm, ileus, erütasyon, rektal kanama, özofajit, glossit, melena, ağız ülseri, gastroint

Endokrin: adrenal korteks yetmezliği

Hemik ve Lenfatik Sistem: ekimoz, trombositopeni, lökositoz, lenfadenopati, agranülositoz, lenfoma benzeri reaksiyon, pansitopeni, peteşi

Metabolik ve Beslenme Bozuklukları : hiperglisemi, hiponatremi, kaşeksi, hiperkalsemi, hipomagnezemi, siyanoz, diabetes mellitus, gut, solunum asidozu, yüksek karaciğer enzimleri, susuzluk

Kas-iskelet sistemi: myastenia

Sinir Sistemi: anormal rüyalar, duygusal değişkenlik, paranoyak reaksiyon, uyku bozukluğu öfori, koordinasyon, stupor, ataksi, konvülsiyon, halüsinasyon, düşmanlık, miyoklonus, psikoz, vertigo, yoksunluk sendromu, ilgisizlik, deliryum, demans, uyuşturucu bağımlılığı, nistagmus, seğirme, duyarsızlaşma, afazi, serebrovasküler kaza, hipotural parastiler

Solunum Sistemi: hipoventilasyon, apne, atelektaz, hemoptizi, astım, hiperventilasyon, pulmoner emboli, laringismus

Cilt ve Ekler : ürtiker, makülopapüler döküntü, alopesi

Özel Duyular: anormal görme, diplopi, kuru gözler, lakrimasyon bozukluğu, hiperaküs

Ürogenital: idrar retansiyonu, hematüri, iktidarsızlık, idrar sıklığı, idrara çıkma bozukluğu, dismenore, kreatinin artışı, idrar aciliyeti

ABD Dışı Deneyimlerden Ek Olumsuz Olaylar

Bağımlılık, bulanık görme, uyuşukluk, disfori, sedasyon, nöbet, fiziksel bağımlılık, biliyer spazm ve ileus

Clinical Presentation

Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.

Treatment of Overdose

In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The opioid antagonists, such as naloxone and naltrexone, are specific antidotes to respiratory depression resulting from opioid overdose. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. Such agents should be administered cautiously to patients who are known, or suspected to be, physically dependent on PALLADONE. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome.

Because the duration of reversal would be expected to be less than the duration of action of hydromorphone in PALLADONE, carefully monitor the patient until spontaneous respiration is reliably re-established. PALLADONE will continue to release hydromorphone adding to the hydromorphone load for up to 24 hours after administration, necessitating prolonged monitoring for at least 24 to 48 hours beyond the overdose. If the response to opioid antagonists is suboptimal or not sustained, additional antagonist should be given as directed in the product's prescribing information.

In an individual physically dependent on opioids, administration of an opioid receptor antagonist may precipitate an acute withdrawal. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

CNS Depressant/Alcohol Interaction

Additive pharmacodynamic effects may be expected when PALLADONE is used in conjunction with alcohol, other opioids, legal or illicit drugs that cause central nervous system depression.

Effects on the Central Nervous System

Hydromorphone produces dose-related respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.

Hydromorphone depresses the cough reflex by direct effect on the cough center in the medulla.

Hydromorphone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic. Marked mydriasis, rather than miosis, may be seen due to severe hypoxia in overdose situations.

Effects on the Gastrointestinal Tract and Other Smooth Muscle

Gastric, biliary and pancreatic secretions are decreased by hydromorphone. Hydromorphone causes a reduction in motility associated with an increase in tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm. The end result is constipation. Hydromorphone also can cause an increase in biliary tract pressure as a result of spasm of the sphincter of Oddi.

Effects on the Cardiovascular System

Hydromorphone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Release of histamine may be induced by hydromorphone and can contribute to opioid-induced hypotension.

Manifestations of histamine release or peripheral vasodilation may include pruritus, flushing, red eyes, and sweating.

Effects on the Endocrine System

Opioids inhibit the secretion of ACTH, cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.

Effects on the Immune System

Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

Absorption

PALLADONE is an extended-release formulation of hydromorphone. Administration of a single PALLADONE dose is characterized by biphasic absorption, a relatively rapid rise to an initial peak concentration, followed by a second broader peak with therapeutic plasma concentrations maintained over the 24-hour dosing interval. The absolute bioavailability of hydromorphone from PALLADONE has not been determined. Under conditions of multiple dosing, the bioavailability of a once-daily dose of PALLADONE is equivalent to the same total daily dose of immediate-release hydromorphone given in divided doses every 6 hours. Dose proportionality has been established in terms of Cmax and AUC for the 12 mg and 24 mg dosage strengths. Dosage form proportionality on a dose-adjusted basis has been demonstrated for three 12 mg capsules to one 32 mg capsule.

In a study comparing 12 mg PALLADONE dosed every 24 hours to 3 mg of immediate-release hydromorphone dosed every 6 hours in healthy human subjects, the two treatments were found to be equivalent in terms of extent of absorption (AUC) (see Figure 1). The extended-release characteristics of PALLADONE resulted in lower steady-state peak levels (Cmax), higher trough levels (Cmin), and an approximately twofold to threefold reduction in the fluctuation seen with the immediate-release hydromorphone tablets.

Figure 1: Steady-State Plasma Hydromorphone Concentration-Time Curves

Steady-state plasma concentrations with PALLADONE were achieved within 2 to 3 days after initiation of dosing. This is consistent with the mean apparent terminal elimination half-life for PALLADONE of approximately 18.6 hours. Hydromorphone did not accumulate significantly after multiple dosing with once-daily administration.

Food had no significant effect on the peak (Cmax), AUC or the elimination of hydromorphone from PALLADONE (see Figure 2).

Figure 2: Single-Dose Palladone™ Pharmacokinetic Profiles

Food Effect

The pharmacokinetics of PALLADONE is not affected by food as indicated by bioequivalence when administered under fed and fasting conditions. Therefore, PALLADONE may be administered without regard to meals.

Distribution

Following intravenous administration of hydromorphone, the reported volume of distribution is 295 L (4 L/kg). Hydromorphone is approximately 20% bound to human plasma proteins.

Metabolism

Hydromorphone is metabolized by direct conjugation, or by 6-keto reduction followed by conjugation. Following absorption, hydromorphone is metabolized to the major metabolites hydromorphone-3glucuronide, hydromorphone-3-glucoside and dihydroisomorphine-6-glucuronide. Also observed were the less prevalent metabolites, dihydroisomorphine-6-glucoside, dihydromorphine and dihydroisomorphine.

Hydromorphone metabolites have been found in plasma, urine and in human hepatocyte test systems. However, it is not known whether hydromorphone is metabolized by the cytochrome P450 enzyme system. Hydromorphone is a poor inhibitor of human recombinant CYP isoforms including CYP1A2, 2A6, 2C8, 2D6, and 3A4 with an IC50 > 50 μM. Therefore, hydromorphone is not expected to inhibit the metabolism of other drugs metabolized by these CYP isoforms.