Caffeine
Caffeine has been noted to produce a variety of gastrointestinal (GI) effects. At therapeutic or nontoxic doses, caffeine can stimulate gastric secretions and may cause GI upset (dyspepsia), nausea, loose stools, and may aggravate gastroesophageal reflux disease (GERD). Occasionally diarrhea is reported. The mild dehydration that caffeine produces may aggravate constipation. A temporary reduction in weight gain has also been reported. In a study comparing caffeine to placebo, the mean difference in weight gain was the greatest after 2 weeks of therapy. Feeding intolerance (8.7%), gastritis (2.2%), and GI bleeding (2.2%) also occurred in the caffeine treatment groups. During a controlled clinical trial of caffeine citrate in premature infants (n = 85 neonates), necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. In a much larger clinical trial (n = 2,000 neonates) evaluating the use of caffeine citrate in apnea of prematurity, necrotizing enterocolitis was not more common in caffeine treated patients compared to placebo. In a study evaluating the effect of caffeine on the splanchnic perfusion after a caffeine loading dose, the blood flow velocity was depressed for 2 to 3 hours after the infusion and slowly returned to baseline after approximately 6 hours. Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools, and lethargy in treated infants. Excessive caffeine intake or intoxication in children, adolescents, and adults may cause vomiting along with other signs of caffeine intoxication. In humans, a caffeine concentration of greater than 50 mg/L may produce toxic symptoms.
Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine’s pharmacologic actions. At therapeutic or nontoxic doses, caffeine can commonly cause nervousness, mild tremor, and heightened attentiveness. Less frequent adverse reactions with usual consumption also include excitement, irritability, insomnia, headache, and muscle twitches. Increased caffeine use among children and adolescents has been associated with insomnia, chronic headache, motor tics, irritability, learning difficulties, and other adverse health effects. After excessive doses, caffeine can cause considerable anxiety. Seizures and delirium are also possible. In humans, a caffeine level of > 50 mg/L may produce toxic symptoms. Other neurologic events have been reported in preterm neonates. In clinical trials of caffeine citrate in preterm neonates, cerebral hemorrhage (intracranial bleeding) was reported in 2.2% of treated patients versus 0% of neonates receiving placebo.
Caffeine is a mild diuretic and patients may have increased urinary frequency. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.
Adverse events to caffeine that have been described in the published literature include alterations in serum glucose such as hypoglycemia and hyperglycemia.
In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury (2.2%), bleeding (2.2%), disseminated intravascular coagulation (2.2%), dyspnea (2.2%), pulmonary edema (2.2%), metabolic acidosis (2.2%), xerosis (2.2%), rash (unspecified) (8.7%), renal failure (unspecified) (2.2%), retinopathy of prematurity (2.2%), and skin breakdown (2.2%). In neonates, intolerance or overdose of caffeine may manifest as tachypnea. No deaths have been reported in relation to overdose of caffeine in neonates.
Too much caffeine may occasionally cause rapid heartbeat. Cardiovascular effects of caffeine have been reported in the literature (i.e., palpitations, sinus tachycardia, increased left ventricular output, and increased stroke volume).
High caffeine intake has been reported to negatively affect sperm quality, including spermatogenesis inhibition). The propensity for caffeine to negatively affect fertility is controversial. Although controversial, infertility, as manifested by increased difficulty in getting pregnant, has been reported in females. Couples who are pursuing pregnancy should probably limit excessive intake of caffeine.
A distinct caffeine withdrawal syndrome has been described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or rebound headache upon caffeine withdrawal.
DHEA
NOTE: Some prasterone, dehydroepiandrosterone, DHEA preparations are a combination of several hormones and/or herbs, and each individual component may need to be evaluated in the presence of adverse reactions. Only adverse reactions pertaining to DHEA are discussed in this monograph. Human side-effect data to date have been collected in non-systematic fashion via the FDA special nutritional adverse effect monitoring system (SNAEMS) or relatively small clinical trials.
DHEA has been observed to cause reversible reductions in HDL cholesterol and total cholesterol in some clinical trials; other trials have not noted changes in the serum lipid profile. DHEA may also exhibit anti-platelet effects. The influence of these changes on the development of side effects, atherosclerosis, or other cardiac-related endpoints is unknown.
In one 3-month study of 28 women with SLE, the following ADRs were noted in the females receiving DHEA: acneiform rash (57%), hirsutism (14%), weight gain (14%), menstrual irregularity (7%), and emotional lability (7%). The statistical significance of these side effects relative to placebo was not determined. Some events commonly associated with SLE and reported as adverse events in clinical trials were less frequent in patients treated with prasterone (GL701) compared with placebo, including muscle pain, nasal and oral ulceration, and hair loss.
Prasterone, DHEA is a hormone with androgenic actions, however, the incidence of androgenic side effects is not known. When androgens are given to women, they may cause virilization, manifested by clitoromegaly, reduced breast size, and deepening of the voice or voice hoarseness. If treatment is discontinued when these symptoms first appear, they usually subside. Prolonged treatment with androgenic substances can lead to irreversible masculinity, so the benefit of DHEA treatment should be offset against the risk of androgen-like side effects.
The effect of prasterone or DHEA supplementation on normal endocrine processes in women is not clear. Women should report any menstrual changes, including amenorrhea, unusual vaginal bleeding, dysmenorrhea, or abdominal bloating to their health care providers. Breast changes, including breast discharge, breast enlargement, breast tenderness, or galactorrhea should also be reported.
Prasterone (DHEA) has androgenic actions, and it is not clear what effect prasterone may have in male patients. Similar to female patients, male patients may experience worsening of acne vulgaris. Male patients may theoretically experience feminization during prolonged therapy with DHEA resulting from inhibition of gonadotropin secretion and conversion of testosterone to estrogens. Feminizing effects in males might include gynecomastia. Feminizing effects secondary to androgens are generally reversible. It is not clear if DHEA would affect testicular function or prostatic function. Symptoms of urinary retention or urinary urgency, prostate pain, or signs of an enlarged prostate in a male patient should prompt clinical evaluation.
Mild peripheral edema can occur with DHEA use as the result of increased fluid retention (in association with sodium retention) and may be associated with mild weight gain.
Prasterone (DHEA) may cause emotional lability. At least one case of possible DHEA-induced mania has been reported in the literature, in a patient predisposed to bipolar illness who was consuming doses >= 300 mg/day PO on a routine basis. There was a temporal association between the time of drug use and the appearance of manic symptoms. Clinicians should be alert to possible alterations in psychiatric status in patients taking this medication for supplemental or medicinal purposes.
Hepatic dysfunction can occur from use of androgenic steroids, especially the oral 17-alpha-alkylandrogens (e.g., methyltestosterone). DHEA does not contain the 17-alkyl group in its structure, however, transient cases of drug-induced hepatitis in humans have been reported in association with DHEA use; these have included a few reports to the FDA Special Nutritionals Adverse Event Monitoring System (SN/AEMS). Liver toxicity has not been reported in human studies, but elevated hepatic transaminases have been reported and confirmed upon rechallenge in some trials. In 1984, the FDA banned the non-prescription (OTC) sale of DHEA due to concern over hepatitis. Clastogenesis has been noted in hepatic tissues of animals exposed to DHEA. DHEA appears to act as a perisoxome proliferator, resulting in liver tumors and nodules in the periportal areas of the liver lobule in rats. DHEA should be discontinued in any patient developing signs or symptoms of potential liver problems, including elevated hepatic enzymes, continued nausea and vomiting, fatigue, jaundice, or severe abdominal pain; the patient should be evaluated.
In studies of male patients with HIV virus infection, side effects attributed to DHEA treatments and confirmed upon rechallenge included nasal congestion, fatigue, headache, and mild insomnia.
Prasterone (DHEA) therapy is reported to cause libido increase. No objective evidence of this side effect exists at this time.
The effect of DHEA on the progression of hormonally-dependent tumors in males or females, or the risk of secondary malignancy, such as breast cancer, is not known. One case-control study of women with ovarian cancer demonstrated higher serum androstenedione and DHEA/DHEAS levels in patients with ovarian tumors versus controls. Whether DHEA supplementation would be associated with similar the serum hormonal profiles is unknown. Male breast cancer, prostate cancer and prostatic hypertrophy can develop due to endocrine epithelial cell growth during therapy with androgens. One case report has been published of a patient with advanced prostate cancer who was symptomatically treated with DHEA. The patient experienced a “flare” of his cancer during the treatment period. A causal relationship has not been established. Widespread use of DHEA supplements in men or women should be discouraged until more is known about potential secondary malignancy risks.
Prasterone, dehydroepiandrosterone (DHEA) is an androgenic hormone and may potentially cause teratogenesis or changes the ability to conceive or carry a viable pregnancy. Dehydroepiandrosterone, DHEA should be considered contraindicated in pregnancy, similar to other androgenic hormones. It is assumed that exogenous DHEA supplementation to a pregnant woman could potentially have deleterious effects on fetal development or viability. No controlled trials of DHEA in primate or human gestation exist. If pregnancy is suspected, pregnancy should be ruled out before continuing DHEA use.
Methionine
Adverse reactions reported following methionine administration include gastrointestinal disorder: Nausea and vomiting and drowsiness
Methylcobalamin
In most cases, methylcobalamin is nontoxic, even in large doses. Adverse reactions reported following methylcobalamin administration include headache, infection, nausea/vomiting, paresthesias, and rhinitis. Adverse reactions following intramuscular (IM) injection have included anxiety, mild transient diarrhea, ataxia, nervousness, pruritus, transitory exanthema, and a feeling of swelling of the entire body. Some patients have also experienced a hypersensitivity reaction following intramuscular injection that has resulted in anaphylactic shock and death. In cases of suspected cobalt hypersensitivity, an intradermal test dose should be administered.
During the initial treatment period with methylcobalamin, pulmonary edema and congestive heart failure have reportedly occurred early in treatment with parenteral methylcobalamin. This is believed to result from the increased blood volume induced by methylcobalamin. Peripheral vascular thrombosis has also occurred. In post-marketing experience, angioedema and angioedema-like reactions were reported with parenteral methylcobalamin.
Hypokalemia and thrombocytosis could occur upon conversion of severe megaloblastic anemia to normal erythropoiesis with methylcobalamin therapy. Therefore, monitoring of the platelet count and serum potassium concentrations are recommended during therapy. Polycythemia vera has also been reported with parenteral methylcobalamin.
Diarrhea and headache.
Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, swollen painful area on the leg.
Naltrexone HCl
Naltrexone can cause hepatocellular injury when given in excessive doses. Naltrexone does not appear to be a hepatotoxin at the recommended doses. The hepatotoxic potential of naltrexone has been described in a placebo-controlled study using a 300 mg/day dose of naltrexone. In this study, 20% of patients experienced elevated hepatic enzymes (3—19 times baseline values). All patients were asymptomatic, and transaminase levels returned to baseline or decreased in a matter of weeks. Other studies of naltrexone doses > 50 mg/day in patients with opiate dependence or alcoholism also resulted in increased hepatic enzymes. Clinical trial data indicate that 7—13% of study patients receiving 380 mg of intramuscular naltrexone experienced elevated hepatic enzymes compared to 2—6% of those on placebo. Hepatitis, elevated hepatic enzymes, and hyperbilirubinemia have been reported in post-marketing reports with naltrexone. Warn patients of the risk of hepatic injury, and advise them to get immediate medical attention if they experience symptoms of acute hepatitis. A high index of suspicion for drug-related hepatic injury is critical if the occurrence of naltrexone-induced liver damage is to be detected at the earliest possible time. Evaluations to detect liver injury are recommended at a frequency appropriate to the clinical situation and to the naltrexone dose. Discontinue naltrexone if symptoms or signs of acute hepatitis develop.
Central nervous system (CNS) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence included headache (>= 7%), dizziness (4—9%), nervousness (>= 4%), insomnia (>= 3%), anxiety (>= 2%), fatigue (>= 4%), drowsiness (<= 2%), increased energy (< 10%), irritability (< 10%), paranoia (< 1%), restlessness (< 1%), confusion (< 1%), disorientation (< 1%), hallucinations (< 1%), nightmares (< 1%), yawning (< 1%), and hot flashes (< 1%). During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol opioid dependence, the following effects were reported more frequently with the active drug than placebo: dizziness or syncope (13% vs 4%), insomnia (6—14% vs 1—12%), headache (3—25% vs 2—18%), drowsiness (4% vs 1%), and anxiety (12% vs 8%). Cerebral arterial aneurysm, seizures, mental impairment, dysgeusia, euphoric mood (euphoria), migraine, ischemic stroke, irritability, disturbance in attention, abnormal dreams, agitation, delirium, hot flashes, and paresthesias were also reported during clinical trials of intramuscular naltrexone; however, the incidence of these effects is not known. CNS effects reported during post-marketing use of naltrexone include abnormal thinking, agitation, anxiety, headache, fatigue, confusion, euphoria, hallucinations, insomnia, nervousness, drowsiness, hot flashes, dizziness, and hyperkinesis. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.
Depression, suicidal ideation, and attempted suicide have been reported in individuals receiving oral naltrexone, placebo, and in concurrent control groups undergoing treatment for alcoholism and opiate dependence. In controlled clinical trials of the extended-release injectable suspension of naltrexone, suicidal ideation, suicide attempts, or completed suicides occurred in 1% of patients and in no patients treated with placebo. In some cases, the suicidal thoughts or behavior occurred after study discontinuation but were in the context of an episode of depression that began while the patient was taking naltrexone. Two completed suicides occurred in patients who were taking naltrexone. Depression-related events associated with premature discontinuation of naltrexone also occurred in about 1% of patients and in no patients treated with placebo. In the 24-week, placebo-controlled, pivotal trial, adverse events involving depressed mood were reported by 10% of patients treated with naltrexone 380 mg IM as compared with 5% of patients treated with placebo. Monitor patients for the development of depression or suicidal thinking. Families and caregivers of patients being treated with naltrexone 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 health care provider. Physicians should be aware that treatment with naltrexone does not reduce the risk of suicide in patients.
In clinical trials of the extended-release injectable suspension of naltrexone, patients who took naltrexone had increases in eosinophil counts (eosinophilia) relative to patients on placebo, but eosinophil counts returned to normal over a period of several months in the patients who continued to take naltrexone. One diagnosed case and 1 suspected case of eosinophilic pneumonia occurred. The pneumonia resolved with antibiotics and corticosteroids. Consider eosinophilic pneumonia if progressive shortness of breath and hypoxia develop and if patients do not respond to antibiotics.
Patients treated with naltrexone 380 mg IM experienced a mean maximal decrease in platelet count of 17,800/mm3 as compared with 2600/mm3 in placebo patients. In randomized controlled trials, naltrexone administration was not associated with an increase in bleeding related adverse events. Idiopathic thrombocytopenic purpura was reported in one patient who may have been sensitized to naltrexone in a previous course of treatment with naltrexone. The condition cleared without sequelae after discontinuation of naltrexone and corticosteroid treatment. In addition, deep vein thrombosis and pulmonary embolism were reported as treatment-emergent adverse reactions during clinical trials of naltrexone suspension for injection; the incidences are unknown.
Gastrointestinal (GI) effects occurring during clinical trials of oral naltrexone for alcohol or opiate dependence include nausea (>= 10%), vomiting (>= 3%), abdominal pain (> 10%), anorexia (< 10%), diarrhea (< 10%), constipation (< 10%), appetite stimulation (< 1%), weight loss (< 1%), weight gain (< 1%), xerostomia (< 1%), flatulence (< 1%), hemorrhoids (< 1%), and peptic ulcer (< 1%). During controlled trials of oral naltrexone 50 mg/day in alcohol dependence, approximately 5% of patients discontinued naltrexone due to nausea. During clinical trials using 380 mg of extended-release injectable naltrexone suspension for alcohol or opioid dependence, the following GI effects were reported more frequently with 380 mg of the active drug than placebo: nausea (33% vs 11%), vomiting (14% vs 6%), diarrhea (13% vs 10%), abdominal pain (11% vs 8%), xerostomia (5% vs 4%), dental pain (toothache 4% vs 2%), and anorexia (14% vs 3%). Weight loss, weight gain, abdominal discomfort, colitis, constipation, flatulence, appetite stimulation, gastroenteritis, gastroesophageal reflux disease (GERD), GI bleeding, hemorrhoids, acute pancreatitis, paralytic ileus, and perirectal abscess were also reported. In post-market experience of oral naltrexone, GI effects including anorexia, nausea, vomiting, abdominal pain, and diarrhea have been reported. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.
Injection site reactions have been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. Of 440 patients who received 380 mg of the extended-release injectable suspension of naltrexone (Vivitrol) in clinical trials for alcohol dependence, 69% had an injection site reaction (pain, tenderness, induration, swelling, or itching) versus 50% of those receiving a placebo injection. Specific injection site reactions that occurred more frequently in the active treatment group than the placebo group included injection site tenderness (45% vs 39%), injection site induration (35% vs. 8%), injection site pain (5% to 17% vs. 1% to 7%), nodules/swelling (15% vs. 4%), itching at the injection site (10% vs. 0%), and injection site ecchymosis (7% vs. 5%). One patient developed an area of induration at the injection site that continued to enlarge after 4 weeks. Eventually, necrotic tissue that required surgical excision developed. The FDA has received 196 reports of injection site reactions including cellulitis, induration, hematoma, abscess, sterile abscess, and tissue necrosis. Sixteen patients required surgical intervention ranging from incision and drainage in the cases of abscesses to extensive surgical debridement in the cases that resulted in tissue necrosis. The extended-release injectable suspension of naltrexone should only be administered intramuscularly (IM); the risk of serious injection site reactions may be increased when Vivitrol is deposited in subcutaneous or fatty tissue. Instruct patients to monitor the injection site and to get medical care if they develop pain, swelling, tenderness, induration, bruising, itching, or redness at the injection site that does not improve or worsens within 2 weeks. Promptly refer patients with worsening injection site reactions to a surgeon.
Urticaria, angioedema, and anaphylactoid reactions (anaphylaxis) have occurred in association with naltrexone administration in both clinical trials and during post-marketing use. Patients should be advised of the potential for serious hypersensitivity reactions while using naltrexone and instructed to seek immediate medical attention in the event of such a reaction.
During clinical trials using 380 mg of intramuscular (IM) naltrexone, infections reported more frequently within the active drug group than the placebo group included nasopharyngitis (7% vs 2%) and influenza (5% vs 4%). Other respiratory or related effects that were reported during IM naltrexone clinical trials included upper respiratory tract infection, advanced HIV disease in HIV-infected patients, bronchitis, chronic obstructive pulmonary disease, dyspnea, laryngitis, pharyngolaryngeal pain, pneumonia, sinus congestion, and sinusitis. Respiratory effects or symptoms of infection occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included nasal congestion, rhinorrhea, sneezing, sore throat, excess mucus, sinus trouble, hoarseness, cough, fever, and dyspnea. Additionally, eosinophilic pneumonia, which may present as dyspnea, coughing, and/or hypoxia, has been reported in association with injectable naltrexone use (see eosinophilic pneumonia).
In clinical trials of intramuscular naltrexone (380 mg) in patients with opioid dependence, 5% of study patients experienced hypertension compared to 3% of those on placebo. Other cardiovascular effects observed during clinical trials of intramuscular naltrexone included angina, atrial fibrillation, congestive heart failure, coronary artery atherosclerosis, myocardial infarction, and palpitations. Cardiovascular effects occurring in less than 1% of patients during clinical trials of oral naltrexone for opiate dependence included epistaxis, phlebitis, edema, increased blood pressure, unspecified ECG changes, palpitations, and sinus tachycardia. Cardiac effects reported during post-marketing use of naltrexone include chest pain (unspecified), palpitations, and changes in blood pressure. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.
During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, the following musculoskeletal effects or pain symptoms were reported more frequently with the active drug than placebo: arthralgia (12% vs 5%), back pain (6% vs 5%), and muscle cramps (8% vs 1%). Myalgia, joint stiffness, limb pain, and muscle spasms have also been reported. Musculoskeletal effects or pain symptoms occurring during clinical trials of oral naltrexone for opiate dependence included arthralgia and myalgia (> 10%), shoulder pain (< 1%), knee or leg pain (< 1%), tremor (< 1%), twitching (< 1%), inguinal pain (< 1%), and side pain. Tremor and myalgia have been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome. Increased creatinine phosphokinase (CPK) concentrations have been associated with naltrexone use. In open-label trials, 16% of patients dosed for more than 6 months had increases in CPK. Increases in 1—2 times the upper limit of normal (ULN) were most common for both the oral naltrexone and IM naltrexone 380 mg groups. Although CPK elevations of 1—2 times ULN were most commonly encountered, elevations as high as 4 times ULN for the oral naltrexone group and 35 times ULN for the IM naltrexone group were noted. However, there were no differences between the placebo and either the oral or IM naltrexone groups with respect to the proportions of patients with a CPK value at least 3 times ULN. No factors other than naltrexone exposure were associated with the CPK elevations.
Dermatologic or related effects occurring during clinical trials of oral naltrexone for opiate dependence included rash (unspecified) (< 10%), oily skin (< 1%), pruritus (< 1 %), acne vulgaris (< 1%), tinea pedis (< 1%), cold sores (< 1%), and alopecia (< 1%). During clinical trials using 380 mg of intramuscular naltrexone suspension, rash occurred more frequently with active drug than placebo (6% vs 4%). Other related effects reported with the intramuscular formulation included night sweats, pruritus, heat exhaustion, and hyperhidrosis. Rash and increased sweating have also been reported during post-marketing use of naltrexone. It is not always possible to distinguish these occurrences from signs and symptoms of naltrexone-induced opiate discontinuation syndrome.
Genitourinary (GU) effects occurring during clinical trials of oral naltrexone included ejaculation dysfunction (delayed ejaculation < 10%), dysuria (< 1%), increased urinary frequency (< 1%), and libido increase or libido decrease (< 1%). Decreased libido and urinary tract infection have been reported with the use of the intramuscular formulation.
Special senses effects (otic, ophthalmic) occurring in less than 1% of patients during clinical trials of oral naltrexone included blurred vision, ocular irritation (burning), light sensitivity (photophobia), eye swelling/ache (ocular inflammation), otalgia, and tinnitus. Unspecified visual impairment has been reported during post-marketing use of oral naltrexone. Conjunctivitis and blurred vision have also been reported with the use of the intramuscular formulation. Retinal artery occlusion has been reported rarely after injection with another drug product containing polylactide-co-glycolide (PLG) microspheres. This event has been reported in the presence of abnormal arteriovenous anastomosis. No cases of retinal artery occlusion have been reported during clinical trials or post-market use of the intramuscular formulation of naltrexone.
Lymphadenopathy and increased white blood cell count have been reported with the use of naltrexone extended-release suspension for injection during clinical trials.
Acute cholecystitis and cholelithiasis have been reported as treatment-emergent adverse effects in patients who received naltrexone extended-release suspension for injection for alcohol and/or opioid dependence; the incidence of these effects is unknown.
General effects occurring during clinical trials of oral naltrexone for opiate dependence included increased thirst (polydipsia) (< 10%), chills (< 10%), swollen glands (< 1%), and cold feet (< 1%). During clinical trials using 380 mg of intramuscular naltrexone suspension for opioid dependence, asthenia was reported more frequently in the active treatment group than the placebo group (23% vs 12%). Other general events observed during clinical trial evaluation of intramuscular naltrexone included chest tightness, chills, face edema, pyrexia, rigors, and lethargy. Malaise and asthenia have been reported during post-market use of oral naltrexone.
During clinical trial evaluation of intramuscular naltrexone suspension, metabolic or nutritional effects including dehydration and hypercholesterolemia were observed; however, the frequencies are unknown. In some individuals, the use of opiate antagonists has been associated with a change in baseline levels of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of these changes is not fully understood.
Abrupt withdrawal precipitated by administration of an opioid antagonist to an opioid-dependent patient may result in a withdrawal syndrome severe enough to require hospitalization, and in some cases management in the intensive care unit. Opioid withdrawal has been precipitated following self-administration of the naltrexone extended-release suspension (e.g., Vivitrol). Inform patients that the injection must be prepared by and administered by a healthcare professional. To prevent precipitation of withdrawal, patients should be opioid-free for a minimum of 7 to 10 days prior to initiation of naltrexone. When transitioning from buprenorphine or methadone, patients may be vulnerable to precipitation of withdrawal symptoms for up to two weeks. Precipitated opioid withdrawal has also been observed in alcohol-dependent patients in circumstances where the prescriber had been unaware of the additional use of opioids or co-dependence on opioids. Make patients aware of the risks associated with precipitated withdrawal and the need to give an accurate account of last opioid use. Studies of naltrexone in alcoholic populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of patients may experience an opioid discontinuation-like symptom complex including, but not limited to, tearfulness, abdominal cramps, bone, muscle, or joint pain, nasal symptoms, and feeling restless. These symptoms may represent the unmasking of occult opioid use or it may represent symptoms attributable to naltrexone. Patients treated for alcohol dependence with naltrexone should be assessed for underlying opioid dependence and for any recent use of opioids prior to initiation of treatment. Because there is no completely reliable method for determining whether a patient has had an adequate opioid-free period, prescribers should always be prepared to manage withdrawal symptomatically with non-opioid medications. A naloxone challenge test may be helpful; however, a few case reports have indicated that patients may experience precipitated withdrawal despite having a negative urine toxicology screen or tolerating a naloxone challenge test (usually in the setting of transitioning from buprenorphine treatment). Withdrawal symptoms and death have been reported during the use of naltrexone in ultra rapid detoxification programs; the causes of death are not known. If rapid transition from agonist to antagonist therapy is considered necessary and appropriate by the healthcare provider, patients should be closely monitored in an appropriate medical setting where precipitated withdrawal can be managed.
Phentermine HCl
Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients.
Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope, or peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia.
Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.
Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.
Urticaria has been reported in patients receiving phentermine.
Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usual recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times than recommended. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommended. Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal. More data are needed to confirm the dependence potential of phentermine-containing obesity products.
Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued rather than the dose increased. The maximum recommended dose should not be exceeded.
Yohimbine HCl
Yohimbine readily crosses the blood-brain barrier and can therefore produce central nervous system adverse reactions. The most common CNS adverse reactions include anxiety, antidiuresis, dizziness, flushing, headache, hypertension, increased motor activity, irritability, nervousness or restlessness, sinus tachycardia, and tremor. Although yohimbine is not administered intravenously, diaphoresis, nausea and vomiting have been reported following IV administration of yohimbine.
Per the FDA (1993 out of print document), natural Yohimbe is a tree bark containing a variety of pharmacologically active chemicals; the major identified alkaloid in yohimbe is yohimbine. Yohimbe is marketed in a number of dietary supplements for body building and ‘enhanced male performance.’ Serious adverse effects, including renal failure (unspecified), seizures and death, have been reported to FDA with products containing yohimbe. Side effects that are well recognized may include central nervous system stimulation that causes anxiety attacks or agitation. At high doses, yohimbine is reported to inhibit monoamine oxidase (MAO). MAO inhibitors (MAOIs) can cause serious adverse effects (like severe hypertension) when taken concomitantly with tyramine-containing foods (e.g., liver, cheeses, red wine) or with over-the-counter (OTC) products containing phenylpropanolamine (PPA). Patients taking yohimbe should be warned to avoid these foods and PPA because of the increased likelihood of adverse effects.
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