Regulatory Decision Summary for Seaford Nifedipine and Lidocaine Hydrochloride Cream

This New Drug Submission (NDS) Clinical / Chemistry and Manufacturing was filed to obtain market authorization for Seaford Nifedipine and Lidocaine Hydrochloride Cream (0.3% nifedipine and 1.5% lidocaine weight /weight) (i) for the treatment of the anal fissures generally associated with anal sphincteral hypertone, (ii) to be used for both acute and chronic anal fissures located endorectal and perianal, (iii) to relieve pain of fissures, (iv) to heal anal fissures, (v) to reduce recurrence of anal fissures, (vi) to reduce mean and resting pressure in patients with anal fissures, (vii) to reduce post-hemorrhoidectomy pain, (viii) to relieve pain of thrombosed hemorrhoids, and (ix) to heal thrombosed hemorrhoids.

Upon review of the submitted data package, Health Canada authorized Seaford Nifedipine and Lidocaine Hydrochloride Cream for adults for the management of chronic primary anal fissures unresponsive to stool softeners and topical anesthetic agents.

This submission was filed as a Submission Relying on Third Party Data (SRTD) according to the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).

The sponsor sought the approval of various indications related to the management of anal fissures, hemorrhoids, and post-hemorrhoidectomy pain. However, the studies provided in support of the indications related to hemorrhoids and post-hemorrhoidectomy pain were not acceptable, primarily due to the deficient study design and/or failed efficacy results.

The proposed indications for anal fissures were supported by the results of one pivotal phase 3 randomized, double-blind, placebo-controlled, parallel-group study (P0001/98) performed in Italy in 110 patients with primary anal fissures for at least two months who were unresponsive to stool softeners and topical anesthetic agents. Patients were randomized in a 1:1 ratio to apply 3 g Seaford Nifedipine and Lidocaine Hydrochloride Cream or 3 g 1.0% hydrocortisone acetate and 1.5% Lidocaine Hydrochloride ointment peri-anally and rectally twice daily for 21 days. The design of the clinical trial was acceptable, and the selected population reflects the indicated population. The primary efficacy endpoint was the rate of patients whose anal fissure was completely or almost completely healed on day 21 of treatment. The main clinically relevant secondary endpoint was the rate of patients with no pain on day 21; however, this and other secondary endpoints were not multiplicity controlled.

After 21 days of treatment, the proportion of patients whose anal fissures were completely or almost completely healed was statistically significantly larger in the group treated with Seaford Nifedipine and Lidocaine Hydrochloride Cream (94.5%) compared to the control group (16.4%), for a between-group difference of 78.1% (p‑value <0.001). Absence of anal pain was reported at a high rate in the Seaford Nifedipine and Lidocaine Hydrochloride Cream group (87.3%) as compared to the control group (10.9%), for a between-group difference of 76.4%.

The safety data from the pivotal P001/98 study showed no adverse reactions, and one case of local hyperemia upon anoscope examination (1.7% of 55 patients in the treatment group). No significant change in blood pressure, heart rate or ECG were reported. The safety data from another phase 3 study, Antro-01-05, conducted in patients with hemorrhoidectomy was also considered given the larger study sample size and more extensive anorectal lesions, which may enhance systemic absorption and adverse systemic effects. 270 patients were randomized 1:1 to receive 3 g twice daily of either Seaford Nifedipine and Lidocaine Hydrochloride Cream or a 1.5% lidocaine cream for 14 days. The results showed that the rates of adverse events and reactions were not significantly different; 1 non drug related serious adverse event was reported in each treatment group. One case of headache attributed to Seaford Nifedipine and Lidocaine Hydrochloride Cream treatment led to treatment discontinuation. No significant changes in blood pressure or heart rate were reported. Post-marketing data did not raise any unexpected safety signals.

The safety profiles of nifedipine and lidocaine are well-known as they have been authorized for use in Canada and internationally for decades. Risks include methemoglobinemia, severe hypotension, worsening of angina pectoris, and heart arrhythmia that could be serious and life threatening. Many potential drug interactions are possible, including with cytochrome P450 enzymes (both nifedipine and lidocaine are metabolized by CYP3A4 and to a lesser extent CYP1A2), as well as with digoxine, anticoagulants, antiarrhythmic drugs, and methemoglobin inducing agents, in addition to beta blocking agents for nifedipine. All known risks have been mitigated by adequate labelling, including contraindications, warnings and precautions, and drug interactions. The risks are further mitigated by the clinical pharmacokinetics data, which showed that mean C_max (maximum blood concentration of drug) levels were below the established toxic levels of nifedipine and lidocaine.

Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine pharmacovigilance activities.

The chemistry and manufacturing information submitted for Seaford Nifedipine and Lidocaine Hydrochloride Cream has demonstrated that the drug substances and drug product can be consistently manufactured to meet the approved specifications.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Seaford Nifedipine and Lidocaine Hydrochloride Cream for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Seaford Nifedipine and Lidocaine Hydrochloride Cream. please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.