Administration: (from Uptodate)
Extended-release formulations:
Capsule, extended release (once daily dosing; eg, Cardizem CD, Tiazac): 120 to 300 mg once daily
Capsule, extended release (twice daily dosing; eg, Cardizem SR): 120 to 300 mg/day in 2 divided doses
Formulations (from Uptodate): Capsule Extended Release 24 Hour, Oral, as hydrochloride: Cardizem CD: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg [contains fd&c blue #1 (brilliant blue)]
Cartia XT: 120 mg, 180 mg, 240 mg
Cartia XT: 300 mg [contains fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40 (allura red ac dye), fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake, quinoline yellow (d&c yellow #10)]
Dilt-XR: 120 mg, 180 mg, 240 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
Taztia XT: 120 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40 (allura red ac dye), fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Taztia XT: 180 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40(allura red ac)aluminum lake, fd&c yellow #6 (sunset yellow), quinoline (d&c yellow #10) aluminum lake, quinoline yellow (d&c yellow #10)]
Taztia XT: 240 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40 (allura red ac dye), fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Taztia XT: 300 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40 (allura red ac dye), fd&c red #40(allura red ac)aluminum lake, fd&c yellow #6 (sunset yellow), quinoline (d&c yellow #10) aluminum lake, quinoline yellow (d&c yellow #10)]
Taztia XT: 360 mg [contains corn starch, fd&c blue #1 (brill blue) aluminum lake, fd&c blue #1 (brilliant blue), fd&c blue #2(indig carmine)aluminum lake, fd&c red #40(allura red ac)aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Tiadylt ER: 120 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Tiadylt ER: 180 mg [contains fd&c blue #1 (brilliant blue)]
Tiadylt ER: 240 mg, 300 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Tiadylt ER: 360 mg [contains fd&c blue #1 (brilliant blue)]
Tiadylt ER: 420 mg
Tiazac: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Generic: 120 mg, 180 mg, 240 mg, 300 mg, 360 mg, 420 mg
Bosentan
Per Uptodate, Bosentan is indicated for raynaud phenomenon in systemic sclerosis. Raynaud phenomenon in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily (Ref). Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information. It is indicated for digital ulcers in systemic sclerosis Digital ulcers in systemic sclerosis (off-label use): Oral: 62.5 mg twice daily for 4 weeks followed by an increase to a maintenance dose of 125 mg twice daily. [2]
Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The RAPIDS-2, ‘RAndomized, double-blind, Placebocontrolled study, studied bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis. It was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc. Methods This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU (‘cardinal ulcer’) to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety. Results Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean±standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment. Conclusions Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs. [3]
RAPIDS-1 studied 96 patients with scleroderma. 1.4 new ulcers in treatment group vs 2.7 in placebo [4]
Videocapillaroscopy showed significant improvement of microcirculatory patterns at T4 (p<0.05). MRSS decreased throughout the study, reaching the statistical significance at T3 and T4. [5]
Limit the use of low-dose aspirin (75 or 81 mg/day) to patients with secondary RP who have a history of ischemic ulcers or other thrombotic events, and who have no additional risks associated with aspirin use. The benefit of antiplatelet therapy with aspirin is overall uncertain because of the lack of evidence overall for its use in patients with RP. There has been only one small trial with treatment using aspirin plus dipyridamole, aspirin alone, or dipyridamole alone in patients with RP, but most had primary RP. Antiplatelet agents appeared to have no effect on symptoms of RP. Aspirin should be avoided in selected patients such as those with SSc who are at a higher risk of gastrointestinal bleeding from underlying gastric antral vascular ectasia. [1]
Epoprostenol (PGI2) is typically administered through a peripheral line, started at a dose of 2 ng/kg per minute, and increased over a period of one to two days, as tolerated, to 4 to 8 ng/kg per minute for a duration of five hours. Epoprostenol has been most widely used for the treatment of idiopathic pulmonary hypertension as well as pulmonary hypertension associated with SSc. A randomized trial including 14 patients with RP found that treatment with IV weekly epoprostenol was associated with a reduction in the frequency and duration of attacks compared with placebo, with a loss in clinical response observed between 8 and 10 weeks after the last infusion. Another randomized trial of epoprostenol for pulmonary hypertension associated with SSc and related disorders showed a favorable but statistically nonsignificant difference in the severity of RP and fewer new digital ulcers in the epoprostenol-treated patients. [1]
In patients with SSc and recalcitrant or recurrent ulcers, add phosphodiesterase (PDE) type 5 inhibitors rather than calcium channel blockers (CCBs) alone. There are limited data suggesting that PDE type 5 inhibitors reduce the number of ulcer formations in patients with SSc. In a trial including 41 patients with RP secondary to SSc, patients were randomly assigned to receive oral sildenafil 100 mg/day (21 patients, mean age 47.2 years) or placebo (20 patients, mean age 41.6 years). After 8 weeks of treatment, sildenafil improved digital blood flow and RP symptoms. A meta-analysis found that PDE type 5 inhibitors were beneficial in ulcer healing compared with placebo in SSc (relative risk 3.28 [95% CI 1.32-8.13]) . [1]
In a Canadian meta-analysis of healing and prevention of digital ulcers in systemic sclerosis efficacy of therapies in healing and preventing digital ulcers (DUs) in systemic sclerosis (SSc; scleroderma) was performed. Randomized controlled trials (RCTs) with outcomes investigating healing or prevention of DUs in SSc and comparing a pharmacologic therapy with placebo or an active agent were included. The pooled risk ratios (RRs) using the fixed-effects model were calculated and heterogeneity was tested using the I(2) statistic. RESULTS of sixty studies were published; 19 were not randomized, and 10 did not give DU quantitative data or no comparison of a different drug, leaving 31 RCTs with a total of 1,989 patients. Quality was 3 of 5 or less for 11 trials. DUs were not the primary outcome in many RCTs. Phosphodiesterase type 5 (PDE-5) inhibitors were significant for DU healing (RR 3.28 [95% confidence interval (95% CI) 1.32, 8.13], P = 0.01). Two large bosentan trials were significant for mean number of new DUs (standardized mean difference [SMD]-0.34 [95% CI -0.57, -0.11], P = 0.004). Oral prostacyclins were not statistically differentfrom placebo, but intravenous (IV) iloprost prevented new DUs (SMD 0.77 [95% CI -1.46, -0.08], P = 0.03). Single trials for atorvastatin and vitamin E were positive in the prevention and healing of DU, respectively. There were many negative trials: antiplatelet therapy, oral N-acetylcysteine, heparin, dimethyl sulfoxide, ketanserin, prazosin, prostaglandin E1, cyclofenil, quinapril, and topical nitroglycerin formulation. CONCLUSION was that given small sample sizes, few comparative trials, and heterogeneity limited the conclusions, the results suggest a role for PDE-5 inhibitors in the healing of DUs; bosentan and IV iloprost may prevent new DUs. From AD McMaster University, Hamilton, Ontario, Canada. [6]
To determine whether a single session of botulinum toxin type A (BTA) injections into both hands more effectively decreases the frequency of systemic sclerosis–associated Raynaud's phenomenon (SSc-RP) episodes than placebo, a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase III trial in patients with SSc-RP assessed the effect of 50-unit BTA or placebo injections into the palms of both hands around each neurovascular bundle during 1 session in winter. The primary end point was the between-group difference in the median change in the number of RP episodes from baseline (day 0) to 4 weeks postinjection. Values between the groups were compared with the Wilcoxon rank-sum test. [7]
Results: Neither the primary nor secondary end points were reached, and results do not support any beneficial effect of palmar BTA injections to treat SSc-RP. [7]
For patients with acute severe ischemia, when oral and/or topical vasodilatory therapy does not quickly result in improvement in digital blood flow and/or when IV PG are not readily available, we suggest digital block or regional block for transient relief of acute digital ischemia, which can provide rapid relief of pain. As needed, we use a digital block for rapid control of pain while arrangements for IV or other therapy are underway. A digital or regional (eg, wrist) block is usually performed with local infiltration of lidocaine or bupivacaine (without epinephrine). These regional nerve blocks for RP have not been systematically evaluated in clinical trials, and their use in this setting is largely based on clinical experience and extrapolation from other clinical settings. This intervention may be thought of as a temporizing measure as there are also no formal studies to define the impact on complications such as recurrent digital ulcers. Side effects include decreased sensation and orthostatic changes but not paralysis. More proximal nerve blocks, such as cervical or lumbar injections, are rarely used unless other approaches have failed. Sometimes it is temporarily effective in reversing acute vasospasm. [1]
Amputation and recurrent ulceration following digital sympathectomy were frequent (14 and 18 percent, respectively). Among patients with RP and SSc with digital ischemia, the perioperative complication rate was 37 percent [1].
Surgical debridement of areas of necrosis and occasionally amputation may be needed for irreversible ischemia. Digital ulcers occur in up to half of patients with SSc. Among 1459 patients with SSc and digital ulcers, ulcers were recurrent in 46.2 percent and chronic in 11.2 percent. Amputation occurred in 7.6 and 15.9 percent of these patients, respectively. Most amputations are minor, involving the distal digit. When proper care is given to digital ulcers, healing typically occurs within 6 to 12 weeks. [1]
