Phentermine HCl / Methylcobalamin Capsules

Phentermine

Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s, there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a ‘Dear Health Care Professional’ letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of exogenous obesity.

Methylcobalamin

Methylcobalamin, or vitamin B12, is a B-vitamin. It is found in a variety of foods such as fish, shellfish, meats, and dairy products. Although methylcobalamin and vitamin B12 are terms used interchangeably, vitamin B12 is also available as hydroxocobalamin, a less commonly prescribed drug product (see Hydroxocobalamin monograph), and methylcobalamin. Methylcobalamin is used to treat pernicious anemia and vitamin B12 deficiency, as well as to determine vitamin B12 absorption in the Schilling test. Vitamin B12 is an essential vitamin found in the foods such as meat, eggs, and dairy products. Deficiency in healthy individuals is rare; the elderly, strict vegetarians (i.e., vegan), and patients with malabsorption problems are more likely to become deficient. If vitamin B12 deficiency is not treated with a vitamin B12 supplement, then anemia, intestinal problems, and irreversible nerve damage may occur.

The most chemically complex of all the vitamins, methylcobalamin is a water-soluble, organometallic compound with a trivalent cobalt ion bound inside a corrin ring which, although similar to the porphyrin ring found in heme, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Methylcobalamin cannot be made by plants or by animals; the only type of organisms that have the enzymes required for the synthesis of methylcobalamin are bacteria and archaea. Higher plants do not concentrate methylcobalamin from the soil, making them a poor source of the substance as compared with animal tissues.

Phentermine

Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic. Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of methamphetamine itself.3 Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct stimulation of the satiety center in the hypothalamic and limbic region.

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.

Methylcobalamin

Vitamin B12 is used in the body in two forms, methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine which is, in turn, required for DNA methylation. The other form, 5-deoxyadenosylcobalamin, is a cofactor needed by the enzyme that converts L-methylmalonyl-CoA to succinyl-CoA. This conversion is an important step in the extraction of energy from proteins and fats. Furthermore, succinyl CoA is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells.

Vitamin B12, or methylcobalamin, is essential to growth, cell reproduction, hematopoiesis, and nucleoprotein and myelin synthesis. Cells characterized by rapid division (epithelial cells, bone marrow, myeloid cells) appear to have the greatest requirement for methylcobalamin. Vitamin B12 can be converted to coenzyme B12 in tissues; in this form it is essential for conversion of methylmalonate to succinate and synthesis of methionine from homocysteine (a reaction which also requires folate). In the absence of coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, 5-methyl tetrahydrofolate, resulting in functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form required by many SH-activated enzyme systems. Through these reactions, vitamin B12 is associated with fat and carbohydrate metabolism and protein synthesis. Vitamin B12 deficiency results in megaloblastic anemia, GI lesions, and neurologic damage (which begins with an inability to produce myelin and is followed by gradual degeneration of the axon and nerve head). Vitamin B12 requires an intrinsic factor-mediated active transport for absorption, therefore, lack of or inhibition of intrinsic factor results in pernicious anemia.

Phentermine

Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity.

According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease, advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma. Likewise, orally disintegrating tablets, are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension. Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further, primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pectoris, syncope, or lower extremity 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 lower extremity edema.

Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be used with caution in patients with thyroid disease.

Phentermine is contraindicated for use during or within 14 days following the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine.

Phentermine is contraindicated in patients with agitated states aggravates these effects or cause an adverse drug reaction. Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety.

The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction. Advise patients to avoid alcohol while taking phentermine.

Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should monitor their blood glucose regularly and follow the recommendations of their health care provider.

Appetite suppressant therapy is not recommend for use in those patients with a history of anorexia nervosa or other eating disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is chemically and pharmacologically related to the amphetamines which have been extensively abused. The possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or drug diversion.

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy. Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Abrupt discontinuation of phentermine after prolonged high doses may result in severe mental depression or extreme fatigue; sleep EEG changes have also been noted. Gradual withdrawal of therapy is recommended. If immediate discontinuation is medically necessary, careful monitoring and symptom management is warranted.

Phentermine is contraindicated during breastfeeding. It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.

Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates.

The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal impairment.

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs. Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation.

Methylcobalamin

Who should not take this medication? Patients with early hereditary optic nerve atrophy, cyanocobalmin hypersensitivity, and those who are pregnant. Your health care provider needs to know if you have any of these conditions: kidney disease; Leber’s disease; megaloblastic anemia; an unusual or allergic reaction to methylcobalamin, cobalt, other medicines, foods, dyes, or preservatives; pregnant or trying to get pregnant; breast-feeding.

Methylcobalamin is contraindicated in patients with methylcobalamin hypersensitivity or hypersensitivity to any of the medication components. Methylcobalamin is also contraindicated in patients with cobalt hypersensitivity because methylcobalamin contains cobalt. In the case of suspected cobalt hypersensitivity, an intradermal test dose should be administered because anaphylactic shock and death have followed parenteral administration of methylcobalamin.

Methylcobalamin should not be used in patients with early hereditary optic nerve atrophy (Leber’s disease). Optic nerve atrophy can worsen in patients whose methylcobalamin levels are already elevated. Hydroxocobalamin is the preferred agent in this patient population (see separate monograph in Less Common Drugs).

Most formulations of methylcobalamin injection contain benzyl alcohol as a preservative. Benzyl alcohol may cause allergic reactions. Methylcobalamin injections should be used cautiously in those patients with benzyl alcohol hypersensitivity. Methylcobalamin, vitamin B12 preparations containing benzyl alcohol should be avoided in premature neonates because benzyl alcohol has been associated with ‘gasping syndrome,’ a potentially fatal condition characterized by metabolic acidosis and CNS, respiratory, circulatory, and renal dysfunction.

Vitamin B12 deficiency can suppress the symptoms of polycythemia vera. Treatment with methylcobalamin or hydroxocobalamin may unmask this condition.

Folic Acid, vitamin B9 is not a substitute for methylcobalamin, vitamin B12 deficiency, although it may improve vitamin B12 megaloblastic anemia. However, exclusive use of folic acid in treating vitamin B12 deficient megaloblastic anemia could result in progressive and irreversible neurologic damage. Before receiving folic acid or methylcobalamin, patients should be assessed for deficiency and appropriate therapy started concurrently. The intranasal formulations are not approved to treat acute B12 deficiency; all hematologic parameters should be normal before beginning the methylcobalamin intranasal formulations. Concurrent iron-deficiency anemia and folic acid deficiency may result in a blunted or impeded response to methylcobalamin therapy.

Certain conditions may blunt or impede therapeutic response to methylcobalamin therapy. These include serious infection, uremia or renal failure, drugs with bone marrow suppression properties (e.g., chloramphenicol), or concurrent undiagnosed folic acid or iron deficiency anemia. The mechanism appears to be interference with erythropoiesis. Patients with vitamin B12 deficiency and concurrent renal or hepatic disease may require increased doses or more frequent administration of methylcobalamin.

Clinical reports have not identified differences in responses between elderly and younger patients. Generally, dose selection for elderly patients should be done with caution. Elderly patients tend to have a greater frequency of decreased hepatic, renal, or cardiac function, and also have concomitant disease or receiving other drug therapy. Start with doses at the lower end of the dosing range.

Phentermine

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and are contraindicated during pregnancy. Safe use of phentermine during pregnancy has not been established; there is no known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Methylcobalamin

Parenteral methylcobalamin is classified as pregnancy category C. Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breastfed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy. The usual daily recommended amounts of methylcobalamin, vitamin B12 either through dietary intake or supplementation should be taken during pregnancy (see Dosage).

Phentermine

Phentermine is contraindicated during breastfeeding. It is not known whether phentermine and its metabolites are excreted in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breastfeeding while taking phentermine is not recommended.

Methylcobalamin

Methylcobalamin is distributed into breast milk in amounts similar to those in maternal plasma, and distribution in breast milk allows for adequate intakes of methylcobalamin by breastfeeding infants. Adequate maternal intake is important for both the mother and infant during nursing, and maternal requirements for vitamin B12 increase during lactation. According to the manufacturer, the usual daily recommended amounts of methylcobalamin, vitamin B12 for lactating women should be taken maternally during breastfeeding (see Dosage). The American Academy of Pediatrics considers vitamin B12 to be compatible with breastfeeding. Consider the benefits of breastfeeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breastfeeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Phentermine

The safety of phentermine when used with other anorexiant agents such as amphetamine, benzphetamine, dexfenfluramine, dextroamphetamine, diethylpropion, ephedrine, fenfluramine, and sibutramine is controversial and concurrent use should be avoided. The role of phentermine in the production of cardiac valvulopathy when combined with dexfenfluramine, fenfluramine, or other medications for weight loss is uncertain. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. Similarly, because phentermine is a sympathomimetic and anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics or psychostimulants for weight loss, including OTC preparations, and herbal products that may contain ephedra alkaloids or Ma huang.

Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable.

Concurrent use of bromocriptine and some sympathomimetics such as phentermine should be approached with caution. One case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen; dichloralphenazone; isometheptene for a headache. A second case involved a post-partum patient receiving bromocriptine who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures, and cerebral vasospasm.

In theory, an interaction is possible between cabergoline, an ergot derivative, and some sympathomimetic agents such as phentermine. Use of the ergot derivative bromocriptine for lactation suppression in conjunction with a sympathomimetic (i.e., isometheptene or phenylpropanolamine) for other therapeutic uses has resulted in adverse effects such as worsening headache, hypertension, ventricular tachycardia, seizures, sudden loss of vision, and cerebral vasospasm.

Concurrent use of dronabinol, THC or nabilone with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity.

Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone, linezolid, or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phenelzine and tranylcypromine appear to produce the greatest risk since these two MAOIs also have intrinsic amphetamine-like activity. In the presence of MAOIs, phentermine and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. It is unclear if selegiline, an inhibitor of MAO type B, can also predispose to this reaction. Phentermine should not be administered during or within 14 days following the use of most MAOIs or drugs with MAO-inhibiting activity. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected. However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics.

The pressor response to some sympathomimetics is exaggerated in patients currently receiving tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics, including phentermine, should be avoided whenever possible.

Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents such as guanadrel, guanethidine, methyldopa or reserpine. Phentermine may displace guanethidine from the neuron and antagonize the neuronal blockade caused by guanethidine. Concomitant use of phentermine with methyldopa or reserpine may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications.

Use caution in combining phentermine with antidiabetic agents. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacodynamic interaction with antidiabetic agents may occur. Diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently.

Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its effects on blood pressure, phentermine should be discontinued several days prior to surgery.

Concurrent use of phentermine and phenothiazines may antagonize the anorectic effects of phentermine. In addition, psychostimulants can aggravate psychotic states.

Although not studied, the concomitant use of ethanol and phentermine may result in an adverse reaction and should be avoided.

Phentermine, like other sympathomimetics, is contraindicated in selected patients with thyroid disease; caution should be used if coadministering thyroid hormones with phentermine.

Atomoxetine has been reported to increase blood pressure and heart rate, probably via inhibition of norepinephrine reuptake. Due to an additive pharmacodynamic effect, phentermine and atomoxetine should be used together cautiously, particular in patients with a history of cardiac disease. Consider monitoring heart rate and blood pressure at baseline and regularly throughout treatment if these agents must be used together.

Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine or the combination of phentermine; topiramate, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving these weight loss aides with bupropion or bupropion-containing combinations. Other side effects might also occur, such as dizziness, blood pressure changes, or other side effects. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss.

Due to the pharmacology of salmeterol, caution and close observation should also be used when fluticasone; salmeterol is used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects based on the pharmacology of salmeterol.

Use phentermine and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.

Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phentermine and the antidepressant fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibition and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.

Methylcobalamin

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Several drugs, including para-aminosalicylic acid, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Monitor for the desired therapeutic response to vitamin B12.

The heavy consumption of ethanol for greater than 2 weeks has been reported to reduce the absorption of Methylcobalamin, vitamin B12. Patients should be aware that heavy, chronic ethanol use may counteract the therapeutic effects of vitamin B12; such patients with regular and chronic ethanol consumption be monitored for the desired therapeutic response to vitamin B12.

Several drugs, including colchicine, have been reported to reduce the absorption of methylcobalamin, vitamin B12. Colchicine has been shown to induce reversible malabsorption of vitamin B12, apparently by altering the function of ileal mucosa. Although further study of these interactions is necessary, patients receiving these agents concurrently should be monitored for the desired therapeutic response to vitamin B12.

In a study of 10 healthy male volunteers, omeprazole, in doses of 20 mg—40 mg per day, caused a significant decrease in the oral absorption of methylcobalamin, vitamin B12. Theoretically this interaction is possible with other proton pump inhibitors (PPIs), although specific clinical data are lacking. Patients receiving long-term therapy with omeprazole or other proton pump inhibitors (PPIs) should be monitored for signs of B12deficiency.

Chloramphenicol can antagonize the hematopoietic response to Methylcobalamin, vitamin B12 through interference with erythrocyte maturation. Chloramphenicol is known to cause bone marrow suppression, especially when serum concentrations exceed 25 mcg/ml. Chloramphenicol should be discontinued if anemia attributable to chloramphenicol is noted during periodic blood studies, which should be done approximately every 2 days during chloramphenicol receipt. Aplastic anemia and hypoplastic anemia are known to occur after chloramphenicol administration. Peripherally, pancytopenia is most often observed, but only 1—2 of the major cell types (erythrocytes, leukocytes, platelets) may be depressed in some cases.

Metformin may result in suboptimal oral vitamin B12 absorption by competitively blocking the calcium-dependent binding of the intrinsic factor-vitamin B12 complex to its receptor. The interaction very rarely results in a pernicious anemia that appears reversible with discontinuation of metformin or with Methylcobalamin, vitamin B12 supplementation. Certain individuals may be predisposed to this interaction. Regular measurement of hematologic parameters is recommended in all patients on chronic metformin treatment; abnormalities should be investigated.

Medications know to cause bone marrow suppression (e.g., myelosuppressive antineoplastic agents) may result in a blunted or impeded response to methylcobalamin, vitamin B12 therapy. Antineoplastics that are antimetabolites for the vitamin may induce inadequate utilization of vitamin B12. However, cancer patients usually benefit from vitamin B12 supplementation. The use of methotrexate may additionally invalidate diagnostic assays for folic acid and vitamin B12; however, this is a diagnostic laboratory test interference and not a drug interaction.

The intranasal forms of methylcobalamin, vitamin B12, should be administered at least 1 hour before or 1 hour after ingestion of hot food or liquids. Hot foods may cause nasal secretions and a resulting loss of medication or medication efficacy. Interactions between foods and oral or injectable forms of methylcobalamin are not expected.

Depressed levels of methylcobalamin, vitamin B12, and abnormal Schilling’s test have been reported in patients receiving octreotide.

The use of anti-infective agents or pyrimethamine may invalidate diagnostic assays for folic acid and vitamin B12; however, these are diagnostic laboratory test interferences and not true drug interactions.

Phentermine

This medicine may be habit-forming with long-term use. Check medicines with healthcare provider. This medicine may not mix well with other medicines. Limit caffeine (for example, tea, coffee, cola) and chocolate intake. Use with this medicine may cause nervousness, shakiness, and fast heartbeat. Use birth control that you can trust to prevent pregnancy while taking this medicine.

Primary pulmonary hypertension, a rare and serious lung disease, has developed in patients who received a combination of phentermine along with fenfluramine or dexfenfluramine. Phentermine may cause this lung disease. This medicine may be habit-forming; avoid long-term use. Tell healthcare provider if you have a history of drug or alcohol abuse. May cause serious heart-related side effects. Tell healthcare provider if you have any heart disease.

If you suspect an overdose, call your local poison control center or emergency department immediately. Signs of a life-threatening reaction. These include wheezing; chest tightness; fever; itching; bad cough; blue skin color; fits; or swelling of face, lips, tongue, or throat. Severe behavioral problems. Chest pain or pressure or fast heartbeat. Severe dizziness or passing out. Very nervous and excitable. Severe headache. Any rash. No improvement in condition or feeling worse.

Phentermine

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.

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.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1.Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
2.Adipex-P (phentermine hydrochloride tablets and capsules) package insert. Sellersville, PA: Teva Pharmaceuticals; 2013 Jan.
3.Zolkowska D, Rothman RB, Baumann MH. Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. J Pharmacol Exp Ther. 2006;318:604-610.
4.Adipex-P (phentermine hydrochloride tablets and capsules) package insert. Sellersville, PA: Teva Pharmaceuticals; 2013 Jan.
5.Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
6.Phentermine hydrochloride package insert. Newtown, PA: KVK-Tech Inc; 2010 April.
7.Steiner E, Villen T, Hallberg M, et al. Amphetamine secretion in breast milk. Eur J Clin Pharmacol 1984;27:123-4.
8.Meridia® (sibutramine) package insert. North Chicago, IL: Abbott Laboratories; 2003 Oct.
9.Fastin® (phentermine) package insert. Philadelphia, PA: Beecham Laboratories; 1987 Oct.
10.Dexedrine® (dextroamphetamine) package insert. Research Triangle Park, NC; GlaxoSmithKline; 2007 Mar.
11.Kulig K, Moore LL, Kirk M, et al. Bromocriptine-associated headache: possible life-threatening sympathomimetic interaction. Obstet Gynecol. 1991;78:941—3.
12.Cesamet™ (nabilone) package insert. Costa Mesa, CA: Valeant Pharmaceuticals International; 2006 May.
13.Foltin RW, Fischman MW, Pedroso JJ, et al. Marijuana and cocaine interactions in humans: cardiovascular consequences. Pharmacol Biochem Behav 1987;28:459—94.
14.Azilect (rasagiline mesylate) tablets. Kansas City, MO: Teva Neurosciences, Inc.; 2014 May.
15.Elavil® (amitriptyline) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2000 Dec.
16.Chan JC, Cockram CS, Critchley JA. Drug-induced disorders of glucose metabolism. Mechanisms and management. Drug Saf 1996;15:135—57.
17.Halothane, USP package insert. North Chicago, IL: Abbott Laboratories; 1998 Mar.
18.Tenuate® (diethylpropion hydrochloride) package insert. Bridgewater, NJ: Aventis Pharmaceuticals; 2003 Nov.
19.Strattera® (atomoxetine) package insert. Indianapolis, IN: Eli Lilly and Company; 2008 May.
20.Serevent® Diskus (salmeterol xinafoate inhalation powder) package insert. Research Triangle Park, NC: GlaxoSmithKline; 2008 Mar.
21.Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.
22.O’Neill PM, Peterson, CA. Weight Loss and Depression in Overweight/Obese Subjects With a History of Depression Receiving Phentermine and Topiramate Extended-Release. Presented at the 166th Annual Meeting of the American Psychiatric Association (APA
23.Bostwick JM, Brown TM. A toxic reaction from combining fluoxetine and phentermine. J Clin Psychopharmacol 1996;16:189—90.
24.Zolkowska D, Rothman RB, Baumann MH. Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. J Pharmacol Exp Ther. 2006;318:604-610.
25.Qsymia (phentermine and topiramate extended-release) package insert. Mountain View, CA: Vivus, Inc.; 2014 Sept.
26.Allison DB, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012;20:330-342.
27.Brintellix (vortioxetine tablets) package insert. Deerfield, IL: Takeda Pharmacueticals America, Inc.; 2014 Jul.
28.Suprenza (phentermine hydrochloride) package insert. Cranford, NJ: Akrimax Pharmaceuticals; 2011 Oct.
29.Phentermine hydrochloride package insert. Newtown, PA: KVK-Tech Inc; 2010 April.
30.Lomaira (phentermine hydrochloride) package insert. Newton, PA: KVK-Tech, Inc.; 2016 Sept.
31.Hendricks EJ, Srisurapanont M, Schmidt SL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). 2014;38:292-298.