Wart Inhibit Ointment

Cimetidine

Cimetidine is a histamine H2-antagonist and inhibits actions of histamine mediated by H2-receptors such as gastric acid secretion and pepsin output. It is used where inhibition of gastric acid secretion may be beneficial, as in peptic ulcer disease, including stress ulceration (Gastrointestinal Drugs), gastro-oesophageal reflux disease (Gastrointestinal Drugs), selected cases of persistent dyspepsia (Gastrointestinal Drugs), scleroderma of the oesophagus, pathological hypersecretory states such as the Zollinger-Ellison syndrome (Gastrointestinal Drugs), and in patients at risk of acid aspiration (Gastrointestinal Drugs) during general anaesthesia or child birth. Cimetidine may also be used to reduce malabsorption and fluid loss in patients with the short bowel syndrome and to reduce the degradation of enzyme supplements given to patients with pancreatic insufficiency.

Imiquimod

Imiquimod is a topical agent for the treatment of actinic keratosis, basal cell carcinoma, and external genital and perianal warts (i.e., condylomata acuminata) caused by human papillomavirus (HPV). Like podofilox, imiquimod can be self-administered by the patient, whereas other treatments for condyloma acuminata (e.g., intralesional interferon alfa, podophyllum resin, trichloroacetic acid) must be administered by a health-care provider. Imiquimod, like other currently available therapies for exophytic genital and perianal warts, does not eradicate HPV or affect the natural history of HPV infection. Despite destruction of HPV warts, latent or subclinical HPV infection can persist and recurrence of visible warts is common. Imiquimod cream was granted final FDA approval for the treatment of condylomata acuminata in March 1997. In March 2004 and July 2004, the FDA approved imiquimod cream for the treatment of actinic keratosis and basal cell carcinoma, respectively.

Cimetidine

Cimetidine blocks the effects of histamine at the receptor located on the basolateral membrane of the parietal cell (designated as the H2-receptor). The result is a reduction of both gastric acid volume and gastric acidity. Cimetidine also decreases the amount of gastric acid released in response to other stimuli including food, caffeine, insulin, betazole, or pentagastrin. Because gastric secretions respond to multiple stimuli, cimetidine does not reduce acid-output as dramatically as the proton-pump inhibiting medications (e.g., omeprazole). Cimetidine does not appear to alter gastric motility, gastric emptying, esophageal pressure, or the secretion rate of the gallbladder or pancreas. Cimetidine also exhibits weak anti-androgenic effects.

In combination with an H1-receptor antagonist, cimetidine can suppress the formation of edema, flare, and pruritus that results from histaminic activity. Human skin mast cells express both H1- and H2-receptors. Stimulation of H2-receptors leads to changes in membrane permeability (activating the cyclic AMP-PKA pathway) causing vasodilation. The resultant dilation develops more slowly and is more sustained, as compared to H1-stimulation. Combination therapy blocks both the initial and delayed histaminic response.

Studies in mice and humans have shown that H2-antagonists have an immunoregulatory effect.1 T-lymphocyte suppressor cells have histamine H2 receptors and cimetidine has been reported to reduce activity of these cells, thus enhancing immune response. There is also some evidence that it enhances cellular immunity, notably natural killer cell activity. This discovery has led to the investigation of cimetidine in disorders associated with alteration of the immune response including eosinophilic fasciitis, herpesvirus infections, mucocutaneous candidiasis, hypogammaglobulinaemia, and various malignancies.

There are reports of benefit from the use of cimetidine in patients with viral warts (Dermatological Drugs and Sunscreens) and an 8-year retrospective analysis of 216 patients with plantar warts reported a success rate of about 80%, although warts recurred in 12 patients. However, controlled studies have failed to show significant benefit, and a review concluded that use of H2-antagonists for warts could not be recommended based on the available evidence.

Imiquimod

The exact mechanism of action of imiquimod is unknown. The manufacturer classifies imiquimod as an ‘immune response modifier.’ A human study revealed that imiquimod induces mRNA encoding cytokines including interferon-alfa at the treatment site. In addition, HPVL1, mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown. Animal data reveal that imiquimod induces cytokines such as interferon-alfa, tumor necrosis factor-alpha, and interleukins 1, 6, and 8.

Genital or perianal warts: Exophytic genital and perianal warts are usually caused by human papillomavirus (HPV) types 6 or 11.Wart clearance was associated with tissue production of interferon-alpha, -beta, and -gamma and tumor necrosis factor-alpha. Clinically, the onset of effect is gradual, with most patients (83%) showing some response to treatment in 4 weeks. Median time to complete clearance was 8 weeks for females and 12 weeks for males; however, wart clearing may take up to 16 weeks. As with most common treatments, imiquimod reduces but does not eliminate the HPV load, even if acetowhitened subclinical lesions are targeted, and thus warts may reappear. The approach offers symptomatic relief, but this relief is generally only temporary. In animal models, imiquimod demonstrates antiviral and antitumor activity. The drug does not possess antiviral or antitumor activity in vitro and the effect of topical therapy on transmission of HPV is unknown.

Actinic keratosis (AK) and other cancerous or pre-cancerous skin lesions: In a study of 18 patients with AK, at week 2 increases from baseline in biomarker levels were reported for CD3, CD4, CD8, CD11c, and CD68 for patients treated with imiquimod cream as compared to vehicle. The clinical relevance of these findings is unknown. In a separate study, a dense mononuclear infiltrate was noted surrounding imiquimod-treated basal cell carcinomas, which was determined to be primarily T-helper lymphocytes. However, a significant portion of these cells also stained positive for CD56 indicating the presence of natural killer cells. Imiquimod’s antitumor effects appear mediated by up regulation of local alpha interferon levels and that natural killer cells may be responsible for tumor response.

Cimetidine

H2 blockers can be used in combination with certain antibiotics to eradicate Helicobacter pylori. When cimetidine is used with antimicrobials, clinicians should be cognizant of possible pseudomembranous colitis occurring. Almost all antibacterial agents have been associated with pseudomembranous colitis (antibiotic-associated colitis) which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea following antibacterial administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. Following diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has been observed to occur over two months or more following discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

Cimetidine is contraindicated in any patient hypersensitive to the drug or its components. Cross-sensitivity in this class of compounds has been observed, so cimetidine should be administered with caution to patients with a history of H2-blocker hypersensitivity. An incidence of cross-reactivity among this class of agents is not currently available. Cimetidine injection multidose vials contain benzyl alcohol as a preservative and should be avoided in patients with benzyl alcohol hypersensitivity.

Cimetidine non-selectively inhibits the hepatic cytochrome P450 oxidative enzymes system and many drug interactions have been described when cimetidine was added to, or discontinued from an established drug regimen. The clinician should review potential drug interactions prior to prescribing cimetidine. Cimetidine should be used cautiously in patients with hepatic disease such as cirrhosis, or in those with renal impairment or renal failure, because cimetidine clearance can be reduced. Reduced doses of cimetidine are recommended in patients with renal impairment; further dose reduction may be necessary if liver impairment is also present. Various types of reversible confusional states have been attributed to cimetidine. While decreased clearance would seem to predispose patients to adverse reactions, hepatic disease and/or renal disease have not been shown conclusively to increase the risk for central nervous system reactions.

Imiquimod

There are no known absolute contraindications to the use of imiquimod. The cream contains benzyl alcohol and parabens; use with caution in patients with known benzyl alcohol hypersensitivity or paraben hypersensitivity. Mild to moderate local skin reactions to the drug are common. Should a severe local skin reaction occur, the cream should be removed. Wash the area with mild soap and water. Treatment with imiquimod can be resumed after the skin reaction has subsided. There is no clinical experience with imiquimod cream therapy immediately following the use of other cutaneously applied drugs; therefore, imiquimod cream administration is not recommended until the skin is healed from any previous drug treatment or surgery. Imiquimod is for topical external use as directed only; avoid accidental exposure to other areas, including nasal, lip, or ocular exposure. Imiquimod cream should only be used for the treatment of biopsy-confirmed superficial basal cell carcinoma in immunocompetent adults, with a maximum tumor diameter of 2 cm on the trunk (excluding the anogenital skin), neck, or extremities (excluding the hands and feet). Safe and effective use of Imiquimod cream for other types of basal cell carcinoma, including fibrosing or sclerosing, Basal Cell Nevus Syndrome, or xeroderma pigmentosum has not been established. Safety and efficacy have not been established for imiquimod cream in repeated treatment of actinic keratosis (i.e., > 1 treatment course in the same 25 cm2 area) or superficial basal cell carcinoma. Additionally, the safety of imiquimod cream applied to areas of skin > 25 cm2 (e.g., 5 cm x 5 cm) for the treatment of actinic keratosis has not been established.

Imiquimod has not been evaluated for the treatment of internal urethral, intra-vaginal, cervical, or rectal human papilloma viral disease and is not recommended for these conditions. The safety and efficacy of imiquimod cream in patients with immunosuppression have not been established. Although only limited data are available, the response rate to imiquimod cream may be lower in patients with immunosuppression or human immunodeficiency virus (HIV) infection than in immunocompetent individuals.

Sunlight (UV) exposure, including artificial sunlight exposure, should be avoided or minimized during treatment of actinic keratosis with imiquimod because of a concern for increasing the risk for sun sensitivity. Patients should be counseled to wear protective clothing (hat) when using imiquimod cream. Patients with sunburn should be advised not to use imiquimod cream until fully recovered. Patients who may have considerable sun exposure (e.g., due to occupation, those with inherent sensitivity to sunlight) should exercise caution when using imiquimod cream. Phototoxicity has not been adequately addressed for imiquimod cream. The enhancement of ultraviolet carcinogenicity is not necessarily dependent upon phototoxic mechanisms. Despite the absence of observed phototoxicity in humans, imiquimod cream shortened the time to skin tumor formation in an animal photo-carcinogenicity study.
Imiquimod cream may weaken barrier contraceptive devices such as condoms and vaginal diaphragms. Therefore, reliance on these devices for birth control is not recommended during treatment of genital/perianal warts.

Due to the potential for enhanced systemic absorption of imiquimod, an occlusive dressing should not be applied to the treatment area. However, non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions.

Imiquimod is classified as FDA pregnancy risk category C. During the topical imiquimod clinical program, 10 women who were treated with imiquimod cream became pregnant. Pregnancy outcome information is available for 3 of the 5 women who chose to continue their pregnancies. All three women delivered full term, normal infants (manufacturer’s data on file). Live infants (mean weight of 3528 +/- 482 g) with no major malformations or other adverse effects were also delivered by 2 women who used imiquimod in the first trimester, by 1 woman who used it in the second trimester, by 2 women who used it in the second and third trimesters, and by 2 women who used it in the third trimester. Use of the 5% cream ranged from three times a week to daily, and the mean duration of use was 5 weeks (range, 1—10 weeks). Some animal studies have demonstrated fetal effects (e.g., increased resorption, decreased fetal weights, delays in ossification, bent limb bones, and exencephaly) at doses 163- to 577-times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparisons (in the presence of maternal toxicity) and at a dose 25- to87-times the MRHD based on AUC comparisons without maternal toxicity. Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. There are no adequate and well-controlled studies in pregnant women; use during pregnancy if the potential benefit justifies the potential risk to the fetus. The CDC states that safety during pregnancy has not been established and recommends against use during pregnancy.

Data are limited regarding use of imiquimod during breast-feeding, and its excretion into human milk is unknown. Based on the drugs low molecular weight (240) and prolonged half-life (24—29 hours), excretion in breast milk is possible; however, because only minimal amounts of the drug are systemically absorbed through the skin, significant presence in breast milk is considered unlikely. The manufacturer advises caution when administering to lactating women. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

The efficacy of the imiquimod cream has not been established in neonates, infants, or children < 12 years of age. Two randomized, vehicle-controlled double-blind studies of 702 pediatric patients (age 2—12 years; median age 5 years) with molluscum contagiosum failed to demonstrate efficacy of imiquimod 5% over placebo. Study participants applied imiquimod 5% or vehicle three times weekly for up to 16 weeks. The complete clearance rate in the first study was 24% in the imiquimod group vs. 26% in the vehicle group. The complete clearance rate in the second study was 24% in the imiquimod group vs. 28% in the vehicle group. The safety and efficacy of imiquimod cream for the treatment of actinic keratosis or superficial basal cell carcinoma in neonates, infants, children, or adolescents < 18 years have not been established. In addition, during use of imiquimod in the genital area, dysuria and the inability to void secondary to severe local reactions have been reported in pediatric female patients.

Imiquimod

Imiquimod is classified as FDA pregnancy risk category C. During the topical imiquimod clinical program, 10 women who were treated with imiquimod cream became pregnant. Pregnancy outcome information is available for 3 of the 5 women who chose to continue their pregnancies. All three women delivered full term, normal infants (manufacturer’s data on file). Live infants (mean weight of 3528 +/- 482 g) with no major malformations or other adverse effects were also delivered by 2 women who used imiquimod in the first trimester, by 1 woman who used it in the second trimester, by 2 women who used it in the second and third trimesters, and by 2 women who used it in the third trimester. Use of the 5% cream ranged from three times a week to daily, and the mean duration of use was 5 weeks (range, 1—10 weeks). Some animal studies have demonstrated fetal effects (e.g., increased resorption, decreased fetal weights, delays in ossification, bent limb bones, and exencephaly) at doses 163- to 577-times the maximum recommended human dose (MRHD) based on area under the curve (AUC) comparisons (in the presence of maternal toxicity) and at a dose 25- to87-times the MRHD based on AUC comparisons without maternal toxicity. Imiquimod was not found to be teratogenic in rat or rabbit teratology studies. There are no adequate and well-controlled studies in pregnant women; use during pregnancy if the potential benefit justifies the potential risk to the fetus. The CDC states that safety during pregnancy has not been established and recommends against use during pregnancy.

Cimetidine

Cimetidine is classified as FDA pregnancy risk category B. Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women. Epidemiological evidence based on the use of cimetidine during the first trimester of human gestation does not suggest an increase in fetal malformations compared to the normal population. However, cimetidine, is known to cross the placenta. Unlike other H2-blockers, cimetidine pharmacologically exhibits some weak anti-androgenic activity that could result in feminism of male fetuses. However, conflicting evidence from in utero exposure in animals exists regarding anti-androgenic effects. There are documented data of efficacy in human pregnancy for ranitidine, and many experts consider this H-2 blocker an effective and safe alternative during pregnancy.

Imiquimod

Data are limited regarding use of imiquimod during breastfeeding, and its excretion into human milk is unknown. Based on the drugs low molecular weight (240) and prolonged half-life (24—29 hours), excretion in breast milk is possible; however, because only minimal amounts of the drug are systemically absorbed through the skin, significant presence in breast milk is considered unlikely. The manufacturer advises caution when administering to lactating women. 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 administered drug, health care providers are encouraged to report the adverse effect to the FDA.

Cimetidine

Cimetidine is secreted into breast milk, usually in concentrations that exceed maternal plasma concentrations. Cimetidine is not usually recommended for use during lactation by the manufacturer. However, in the absence of reported adverse events in infants, the American Academy of Pediatrics and other experts consider the drug usually compatible with breast-feeding. Although also excreted in breast milk, other H2-blockers might be considered alternatives due to the fact that they do not typically have anti-androgenic actions, and would not inhibit infant hepatic enzyme activity should the infant be prescribed an interacting medication. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. In one case, a patient with galactorrhea and hyperprolactinemia on cimetidine was switched to ranitidine with resolution of her symptoms. Of all H2-blockers, famotidine is excreted least in breast milk.

Imiquimod

The most common adverse events associated with use of imiquimod are local skin reactions and application site reactions such as itching, burning, stinging, induration, tenderness, erythema, papule, soreness, bleeding, swelling, skin irritation, pain, rash (unspecified), cellulitis, and excoriation. Most of these application site reactions occurred in < 5% of patients with the exception of pruritus, which occurred in 16—32% of imiquimod 5% recipients as compared with 3—4% of the 2.5% or 3.75% cream recipients. Intense local inflammatory reactions including skin weeping or erosion can occur after few applications of imiquimod and may necessitate a rest period of several days. In trials, 7—32% needed a rest period. Local skin reactions in the treatment area included erythema (58—100%), scabbing/crusting (79—93%), edema (12—78%), skin erosion/skin ulcer (4—66%), weeping/exudate (22—51%), flaking/scaling/xerosis (88—93%), vesicles/vesicular rash (2—9%), and induration (7—84%). Other adverse reactions reported include eczema vaccinatum (2%), alopecia (1%), papules (2%), sensitivity, application site swelling, cheilitis (2%), and dermatitis. Tingling at the application site, exfoliative dermatitis, erythema multiforme, skin hyperpigmentation (possibly permanent), skin hypopigmentation (possibly permanent skin discoloration), and hypertrophic scar have all been noted in post-marketing reports. Angioedema has also been noted postmarketing and may be difficult to differentiate from a local skin reaction.Uncircumcised males treating warts under the foreskin should pull back the foreskin and clean the area daily to help avoid severe penile skin reactions, like stricturing. Adverse reactions are more frequent and intense if imiquimod 5% cream is administered once daily rather than the currently recommended 3-times weekly regimen for the treatment of external genital warts. Also, avoid use of multiple imiquimod products on the same area because of a potential increased risk for and severity of local skin reactions. If a severe local reaction occurs, the cream should be removed by washing with mild soap and water. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Treatment can be resumed after the skin reaction has subsided.

Fever (<= 3%), rigors (1%), influenza-like symptoms (< 1% to 4%), lymphadenopathy (2—3%), and chills were noted with imiquimod receipt during clinical trials. Lymphadenopathy resolved in all patients by 4 weeks after treatment completion. Of note, fever and chills may be flu-like signs; consider an interruption of dosing and an assessment of the patient. Infectious and inflammatory adverse events associated with imiquimod during clinical trials included upper respiratory tract infection (3—15%), sinusitis (2—7%), urinary tract infection (1—3%), general viral infection (1%), rhinitis (3%), pharyngitis (1%), fungal infection (2—11%), herpes simplex (3%), and herpes zoster. Treatment site infections were noted in 1—3.23% of patients and required a rest period and antibiotics. Tinea cruris was noted during post-marketing reports.

Proteinuria, dysuria, and urinary rentention have been noted in post-marketing reports. Imiquimod can cause severe local inflammatory reactions of the female external genitalia, which can lead to vulvar swelling. Severe vulvar swelling can cause urinary retention. Dosing should be interrupted or discontinued for severe vulvar swelling.

Central nervous system and psychiatric adverse events reported during imiquimod clinical trials included headache (2—8%), dizziness (< 1% to 3%), and anxiety (< 1% to 1%). Other neuropsychiatric events noted during post-marketing reports included agitation, cerebrovascular accident (stroke), convulsions/seizures (including febrile convulsions), depression, insomnia, multiple sclerosis aggravation, paresis, and suicide.

Adverse events reported during imiquimod clinical trials included fatigue (1—4%), lethargy, back pain (1—4%), arthralgia (1—3%), and myalgia (1%). Of note, flu-like signs and symptoms may include fatigue, myalgias, arthralgias, or malaise; consider an interruption of dosing and an assessment of the patient for flu-like symptoms.

Gastrointestinal adverse events reported during imiquimod clinical trials included diarrhea (1—3%), vomiting (< 1% to 1%), dyspepsia (1—2%), nausea (1—4%), and anorexia (<= 3%). Abdominal pain and abnormal liver function were noted in post-marketing reports. Of note, nausea may be associated with flu-like symptoms; consider an interruption of dosing and an assessment of the patient for flu-like symptoms.

Imiquimod may cause a new primary malignancy. Squamous cell carcinoma was reported in 4% of patients during imiquimod clinical trials as compared with 2% of vehicle recipients. Lymphoma has been noted in postmarketing reports.

Cough was reported in < 1% to 2% of patients during imiquimod clinical trials. Dyspnea was noted in post-marketing reports.

Pancytopenia, anemia, leukopenia, and thrombocytopenia (including idiopathic thrombotic thrombocytopenic purpura (TTP)) have all been noted in post-marketing reports of imiquimod.

Thyroiditis and Henoch-Schonlein purpura syndrome, a systemic vasculitis, have been noted in post-marketing reports for imiquimod. Cautious use of imiquimod is advised for patients with pre-existing autoimmune conditions because imiquimod activates immune cells.

Cimetidine

Mild to severe headache occurred in 2.1% of patients who received cimetidine 800 mg/day (n = 2225) and 3.5% of patients who received 1600 mg/day (n = 924) compared with 2.3% of patients who received placebo (n = 1897) in clinical trials. Dizziness and drowsiness, most cases mild, were reported in approximately 1% of patients who received 800 mg/day or 1600 mg/day in clinical trials. Mental confusion, agitation, psychosis, depression, anxiety, hallucinations, disorientation, have been reported mostly in severely ill patients. These central nervous system adverse effects usually developed within 2—3 days after starting and resolved within 3—4 days of stopping cimetidine therapy.

Rare cases of thrombocytopenia (3 cases per million patients) and decreased white blood counts such as neutropenia and leukopenia (1 case per 100,000 patients) or agranulocytosis (3 cases per million patients) have been reported with cimetidine therapy. Some cases have recurred on rechallenge. Pancytopenia, aplastic anemia, and immune hemolytic anemia have also been reported rarely.

Gynecomastia has been reported in patients who received cimetidine therapy for longer than 1 month. Gynecomastia occurred in approximately 4% of adult patients with pathological hypersecretory conditions and in 0.3% to 1% of patients with other conditions in clinical trials. Galactorrhea and hyperprolactinemia have been reported in patients taking cimetidine. In one case, a patient with galactorrhea and hyperprolactinemia on cimetidine was switched to ranitidine with resolution of her symptoms. Although reversible impotence (erectile dysfunction) was reported in patients with pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome) and mostly in patients who received high doses of cimetidine for > 12 months (mean, 38 months; range, 12-79 months), large surveillance studies have not shown an increased risk of erectile dysfunction in patients who received a regular cimetidine dosage.

Dose-related elevated hepatic enzymes (e.g., increased transaminase levels) have been reported with cimetidine therapy; however, most transaminase level elevations did not worsen with continued therapy and returned to normal by the end of therapy. Cholestatic (cholestasis) or mixed cholestatic hepatocellular effects and pancreatitis have also occurred rarely, most cases reversible. There has been 1 report of biopsy proven periportal hepatic fibrosis. Rarely, fatal hepatic injury has been reported with H2-receptor antagonist use.

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.

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