Compounded Topical Pain Creams: Review of Select Ingredients for Safety, Effectiveness, and Use (2020)
Chapter: Appendix G: Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams
Appendix G
Potential Adverse Effects from Oral Administration of 20 Active Pharmaceutical Ingredients Commonly Used in Compounded Topical Pain Creams
As discussed in Chapter 6, evidence is inadequate to quantify the extent to which the active pharmaceutical ingredients (APIs) reviewed in this report are absorbed and present at local, regional, or systemic levels. Given the limited data, little is known regarding the relative risk for adverse effects caused by systemic absorption. To consider the potential safety concerns for the systemic absorption of APIs in this report, below is a summarized list of the known adverse events derived from the U.S. Food and Drug Administration (FDA)-approved product labels and data derived from Micromedex, a pharmaceutical database resource.
TABLE G-1
Adverse Events Associated with Systemic Absorption of Active Pharmaceutical Ingredients Used in Compounded Topical Pain Creams
| Drug Product | Formulation(s) | Drug Class | FDA-Approved Pain Indications | Off-Label/Non-FDA Uses for Pain |
|---|---|---|---|---|
| Amitriptyline | Oral | Tricyclic antidepressants | None | Fibromyalgia, postherpertic neuralgia |
| Baclofen | Oral, intrathecal | Skeletal muscle relaxant | Muscle spasms | Trigeminal neuralgia, peripheral neuropathy |
| Bupivacaine | Injection | Local anesthetic | None | Pain |
| Cannabidiol | Oral | Cannabinoid | None | None |
| Carbamezapine | Oral | Anticonvulsants | Trigeminal neuralgia | None |
| Clonidine | Transdermal | Alpha2 adrenergic agonist | None | None |
| Clonidine HCl | Epidural, oral | Alpha2 adrenergic agonist | None | Muscle spasms |
| Cyclobenzaprine | Oral | Skeletal muscle relaxant | Skeletal muscle spasm | Fibromyalgia |
| Dexamethasone | Oral, ophthalmic, injection | Adrenal corticosteroid | None | None |
| Doxepin | Oral, topical | Tricyclic antidepressants | None | Chronic pain |
| Gabapentin | Oral, topical | Anticonvulsants | Postherpetic neuralgia | Fibromyalgia, diabetic peripheral neuropathy |
| Example Adverse Effects from FDA-Approved Label | Example Adverse Effects from Micromedex (2019) |
|---|---|
| Cardiovascular, the CNS and neuromuscular, anticholinergic, allergic, hematologic, gastrointestinal, and endocrine adverse reactions (Sandoz, 2014) | Black box warning for increased suicidal thoughts; cardiac arrhythmias |
| Drowsiness, dizziness, and weakness (Metacel Pharmaceuticals, 2019) | Gastrointestinal bleeding |
| Excitation and/or depression of the CNS system as well as cardiovascular adverse reactions (Pfizer, 2012) | Cardiac arrest, respiratory depression |
| Somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, asthenia, rash, sleep disorders, and infections (GW Pharmaceuticals, 2018) | Increased suicidal thoughts; increased liver enzymes |
| Dizziness, drowsiness, unsteadiness, nausea, and vomiting adverse reactions. The most severe reactions observed have been in the hemopoietic system, skin, liver, and cardiovascular system (Novartis, 2009) | StevensJohnson syndrome, toxic epidermal necrolysis, atrioventricular block, syncope, liver failure |
| Dry mouth, drowsiness, fatigue, headache, lethargy, and sedation (Boehringer Ingelheim Pharmaceuticals, 2011) | Atrioventricular block |
| Dry mouth, drowsiness, dizziness, constipation, and sedation (Boehringer Ingelheim Pharmaceuticals, 2009) | Atrioventricular block |
| Drowsiness, dry mouth, fatigue, and headache (McNeil Consumer Healthcare, 2013) | Cardiac dysrhythmia, heart block, myocardial infarction, syncope |
| Allergic reactions, cardiovascular, dermatologic, endocrine, fluid and electrolyte disturbances, gastrointestinal, metabolic, musculoskeletal, neurological/psychiatric, and ophthalmic adverse reactions (Fera Pharmaceuticals, 2004) | Cardiomyopathy, hyperglycemia, pancreatitis |
| Burning/stinging at the site of application, drowsiness, dry mouth, pruritus, and fatigue (Bioglan Pharma, 2002) | Ventricular arrhythmia, thrombocytopenia, suicidal thoughts, kidney damage |
| Dizziness, somnolence, and peripheral edema (Pfizer, 2010a) | StevensJohnson syndrome |
| Drug Product | Formulation(s) | Drug Class | FDA-Approved Pain Indications | Off-Label/Non-FDA Uses for Pain |
|---|---|---|---|---|
| Ketamine | IV, IM | Local anesthesia | None | Acute pain |
| Lidocaine | Rectal, topical | Local anesthetic | Postherpetic neuralgia | Diabetic neuropathy, acute pain |
| Meloxicam | Oral | NSAID | Osteoarthritis, rheumatoid arthritis | None |
| Memantine | Oral | NMDA receptor antagonist | None | None |
| Naproxen | Oral | NSAID | Rheumatoid arthritis, osteoarthritis | None |
| Nifedipine | Oral | Calcium channel blocker | None | None |
| Orphenadrine | Injection, oral | Skeletal muscle relaxant | Musculoskeletal pain | None |
| Pentoxyifyline | Oral | Vasoactive phosphodiesterase inhibitor | None | None |
| Topiramate | Oral | Anticonvulsants | Migraine prophylaxis | None |
| Tramadol | Oral | Opioid agonist | Chronic pain | Cancer pain |
NOTE: CNS = central nervous system; FDA = U.S. Food and Drug Administration; HCl = hydrochloride; IM = intramuscular; IV = intravenous; NMDA = NmethylDaspartate; NSAID = nonsteroidal antiinflammatory drug; REMS = Risk Evaluation and Mitigation Strategy.
| Example Adverse Effects from FDA-Approved Label | Example Adverse Effects from Micromedex (2019) |
|---|---|
| Cardiovascular, respiratory, ocular, genitourinary, psychological, neurological, and gastrointestinal adverse reactions (JHP Pharmaceuticals, 2012) | Bradyarrhythmia, cardiac dysrhythmia, respiratory depression |
| Application site reactions such as irritation, erythema, and pruritus (Scilex Pharmaceuticals, Inc., 2018) | |
| Diarrhea, upper respiratory tract infections, dyspepsia, and influenzalike symptoms (Boehringer Ingelheim Pharmaceuticals, 2012) | Black box warning for increased risk of cardiovascular events, gastrointestinal bleeding and ulceration |
| Dizziness, headaches, confusion, and gastrointestinal adverse effects (Forest Pharmaceuticals, 2013) | Cerebrovascular accident, seizures, kidney failure |
| Gastrointestinal, the CNS, dermatologic, cardiovascular and special senses disturbances (visual and hearing) adverse reactions (Roche, 2007) | Black box warning for increased risk of cardiovascular events, gastrointestinal bleeding and ulceration |
| Peripheral edema, headache, dizziness, fatigue, nausea, and constipation adverse reactions (Bayer Healthcare, 2011; Pfizer, 2010b) | Myocardial infarction, ventricular arrhythmia, suicidal thoughts, kidney damage |
| Dry mouth, tachycardia, palpitation, urinary hesitancy or retention, and blurred vision (3M Pharmaceuticals, 2006) | Palpitations, tachyarrhythmia |
| Cardiovascular, digestive, and nervous system adverse reactions (Validus Pharmaceuticals, LLC, 2016) | Thrombocytopenia |
| Paresthesia, anorexia, and weight loss (Janssen Pharmaceuticals, Inc., 2017) | Dermatologic: Erythema multiforme, StevensJohnson syndrome, toxic epidermal necrolysis |
| Constipation, nausea, dizziness, and headache (Johnson & Johnson, 2009) | Black box warning for addiction, abuse, misuse. Required REMS by FDA. Respiratory depression, accidental ingestion, sedation, coma, and death if used with benzodiazepines or alcohol |
TABLE G-2
Potential Drug–Drug Interactions for Select APIs (Oral Administration)
| Drug Product | Potentially Major or Life-Threatening Drug–Drug Interactions |
|---|---|
| Amitriptilyne | Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of CYCLOBENZAPRINE and TRYCYCLIC ANTIDEPRESSANTS may result in increased risk of serotonin syndrome. |
| Baclofen | Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression. |
| Carbamazepine | Concurrent use of TRAMADOL and SEROTONERGIC CYP3A4 INDUCERS may result in increased risk of serotonin syndrome and reduced TRAMADOL plasma concentrations. |
| Clonidine | Concurrent use of DOXEPIN and CLONIDINE may result in decreased antihypersensitive effectiveness. |
| Clonidine HCI | Concurrent use of DOXEPIN and CLONIDINE may result in decreased antihypersensitive effectiveness. |
| Cyclobenzaprine | Concurrent use of CYCLOBENZAPRINE and TRICYCLIC ANTIDEPRESSANTS may result in an increased serotonin syndrome. Concurrent use of CYCLOBENZAPRINE and TRAMADOL may result in an increased risk of respiratory and CNS depression; increased risk of serotonin syndrome; and an increased risk of paralytic ileus. |
| Dexamethasone | Concurrent use of CORTICOSTEROIDS and NSAIDS may result in an increased risk of gastrointesinal ulcer or bleeding. |
| Doxepin | Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of TRAMADOL and SEROTONERGIC AGENTS WITH ANTICHOLINGERIC PROPERTIES may result in increased risk of paralytic ileus and increased risk of serotonin syndrome. |
| Ketamine | Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression. |
| Meloxicam | Concurrent use of MELOXICAM and NSAIDS AND SALICYLATES may result in increased risk of bleeding. Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. |
| Memantine | Concurrent use of MEMANTINE and SELECTED NMETHYLDASPARATE ANTAGONISTS may result in increased adverse events of NmethylDasperate agonists. |
| Naproxen | Concurrent use of NSAIDS and TRICYCLIC ANTIDEPRESSANTS may result in an increased risk of bleeding. Concurrent use of CORTICOSTEROIDS and NSAIDS may result in increased risk of gastroinstestinal ulcer or bleeding. |
| Nifedipine | Concurrent use of NIFEDIPINE and CYP3A4 INDUCERS may result in decreased NIFEDIPINE exposure. |
| Orphenadrine | Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of paralytic ileus; increased risk of respiratory and CNS depression. |
| Drug Product | Potentially Major or Life-Threatening Drug–Drug Interactions |
|---|---|
| Pentoxyfilline | Concurrent use of PENTOXYFILLINE and NSAIDS may result in an increased risk of bleeding. |
| Topiramate | Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression. |
| Tramadol | Concurrent use of TRAMADOL and CNS DEPRESSANTS may result in an increased risk of respiratory and CNS depression. |
NOTE: CNS = central nervous system; NSAIDS = nonsteroidal antiinflammatory drugs.
SOURCE: Micromedex, 2019.
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